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PTOMAINES  AiNl)  LEUCOMAINES, 


PUTREFACTIVE  AND  PHYSIOLOGICAL  ALKALOIDS. 


BY 


VICTOR  C.  VAUGHAN,  Ph.D.,  M.D., 

PROFESSOR  OF  HVGIENF  AM)  PHYSIOLOGICAL  CHEMISTRY  IN  THE  UNIVERSITY  OF  MICHIGAN, 
AND  DIRECTOR  OF  THE  HYGIENIC  LABORATORY  ; 


FREDERICK  G.  NOYY,  M.S., 

INSTRUCTOR  IN  HYGIENE  AND  PHYSIOLOGICAL  CHEMISTRY  IN  THE   UNIVERSITY  OP  MICHIGAN. 


PHILADELPHIA: 

LEA  BROTHEES  &  CO. 

1888. 


Entered  acfiording  to  Act  of  Congress  in  the  year  1888,  by 

LEA   BROTHEES    &   CO., 

In  the  Office  of  the  Librarian  of  Congress  at  Washington,  I).  C. 


DOR  NAN,     PKINTEre, 
PHILADELPHIA. 


TO 


ALBERT  B.  PRESCOTT,  Pn.D.,  M.D.,  RC.S., 

DIRECTOR   OF  THE   CHEMICAL   LABORATORY    IX   THE   UNIVERSITY   OF   MICHIGAN, 


THIS  LITTLE  WORK 


IS  RESPECTFULLY  DEDICATED 


AS  A  SLIGHT  TOKEN'  OF  THE  HIGH  ESTEEM  IX  WHICH 


HE  IS  HELD  BY  HIS  FORMER  STLDENTS, 


THE  AUTHORS. 


Digitized  by  the  Internet  Archive 

in  2010  with  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/ptomainesleucomaOOvaug 


PREFACE, 


WiTHix  the  past  ten  years  much  has  been  said  and 
written  concerning  the  basic  substances  formed  during  the 
putrefaction  of  organic  matter,  and  those  which  are  pro- 
duced by  the  normal  tissue  changes  in  the  living  organism. 
Many  investigators  have  given  their  whole  time  and  atten- 
tion to  the  study  of  these  substances  and  important  discov- 
eries have  been  made  and  much  light  has  been  thrown  upon 
what  have  heretofore  been  considered  problems  in  medical 
science.  To  collect,  arrange,  and  systematize  the  facts 
concerning  ptomaines  and  leucomaines  has  been  our  first 
object.  Although  many  short  essays,  some  of  them  of 
great  value,  have  been  written  with  the  above-mentioned 
object  in  view,  the  present  work  may  be  regarded  as  the 
first  attempt  to  make  this  collation  embrace  everything  of 
importance  on  this  subject.  In  endeavoring  to  accomplish 
this  object  we  have  met  with  many  difficulties.  The  original 
reports  of  the  various  investigators  are  scattered  through 
the  pages  of  medical  and  scientific  journals,  transactions  of 
societies,  monographs,  government  reports,  etc.  However, 
with  few  exceptions  we  have  been  able  to  obtain  the  original 
reports,  and  Ave  think  that  we  have  included  everything  of 
importance  published  up  to  the  present  year  (1888). 


VI  CONTENTS. 

To  the  physician  the  facts  which  have  been  made  known 
concerning  the  putrefactive  and  physiological  alkaloids  must 
be  of  great  value,  and  if  this  little  work  furnishes  the 
means  by  which  members  of  the  profession  may  become 
better  acquainted  with  the  nature  of  those  poisons  which 
are  introduced  from  without,  and  those  which  are  gener- 
ated within  the  body  of  man,  the  object  of  its  authors  will 
be  accomplished. 

UxiVEESiTY  OF  MiCHiGAX,  July,  1888. 


CONTENTS. 


CHAPTER  I. 

PAOE 

Definition  and  Historical  Sketch  of  Ptomaines        .      13 

CHAPTER   n. 

Foods  Containing  Poisonous  Ptomaines:  Poisonous 
Mussel,  Poisonous  Sausage,  Poisonous  Ham,  Canned 
Meats  and  Fruits,  Poisonous  Claeese,  Milk,  Ice-cream, 
and  Bread         .........       34 

CHAPTER   III. 

The  Relation  of  Ptomaines  to  Disease.  How  Germs 
induce  Disease.  A  Classification  of  Infectious  Diseases: 
Anthrax,  Cholera,  Tetanus,  Typhoid  Fever,  Cholera 
Infantum 86 

CHAPTER   IV. 

The  Importance  of  Ptomaines  to  the  Toxicologist. 
Coniine-like  Substances,  Nicotine,  Strychnine,  Morphine, 
Atropine,  Digitaline,  Veratrine,  Delphinine,  Colchicine     110 

CHAPTER  V. 

Methods  of  Extracting  Ptomaines.  Ptomaines  in  Re- 
agents. The  Stas-Otto  Method,  Dragendorff 's  Method, 
Brieger's  Method,  the  Methods  of  Gautier  and  Etard. 
Remarks  upon  the  Methods     ......     123 


Vlll  PREFACE. 

CHAPTER  VI. 

;  PAGE 

Chemistry  of  the  Ptomaines.  Primary  Amines,  Dia- 
mines, etc.,  the  Ctioline  Group,  other  Oxygen-containing 
Bases,  Undetermined  Ptomaines.     Tables       .         .         .     141 

CHAPTER   VII. 

Chemistry  of  the  Leucomaines.      Uric   Acid   Group, 

Creatinine  Group,  Undetermined  Leucomaines.     Tables     225 

CHAPTER  VIII. 

The  Pathological  Importance  of  the  Leucomaines    .    289 

,  CHAPTER   IX. 

Literature:  Ptomaines,  Leucomaines         ....     296 


PTOMAINES  AND  LEUCOMAINES. 


INTRODUCTIOJSr. 

We  may  divide  diseases  into  two  classes,  the  infectious 
and  tlie  autogenous,  those  introduced  from  without  and 
those  originating  within  the  organism.  The  study  of  the 
infectious  diseases  has  been  pursued  with  great  diligence  in 
recent  years,  and  many  brilliant  results  have  been  reached, 
but  the  question,  How  do  germs  induce  disease  ?  remained 
without  a  satisfactory  answer  until  it  was  discovered  that 
they  produce,  by  their  growth,  chemical  poisons,  pto- 
maines, that  the  absorption  of  these  poisons  is  followed  by 
the  symptoms  of  the  disease,  and  that  each  specific,  patho- 
genic microorganism  produces  its  own  characteristic  poison. 
In  infectious  diseases  the  chemical  poison  is  really  formed 
within  the  body,  but  the  active  agent,  the  germ,  causing 
the  formation  of  the  poison,  is  introduced  from  without. 
It  is,  therefore,  proper  to  speak  of  these  diseases  as  having 
their  origin  outside  of  the  body.  Their  spread  is  to  be 
arrested  by  the  destruction  of  the  germ,  by  isolation  and 
disinfection.  Their  treatment  consists  of  attempts  to  de- 
stroy the  microorganism  which  has  already  found  lodge- 
ment within  the  body,  or,  failing  in  this,  to  antagonize  the 
effects  of  the  poison  and  to  maintain  life  until  the  germ, 
weakened  by  successive  generations  of  growth  or  poisoned 

2 


14  INTRODUCTION". 

by  its  own  products,  ceases  to  manifest  its  ill  effects,  and 
the  disease  terminates  by  self-limitation. 

On  the  other  hand,  the  autogenous  diseases  owe  their 
existence  to  disturbances  between  tissue  metabolism  and 
excretion.  They  are  prevented  by  keeping  these  functions 
of  the  body  in  harmony.  They  are  treated  by  hastening 
elimination  or  by  retarding  or  modifying  metabolism  or  by 
both. 


CHAPTER   I. 

DEFIXITIOX  AXD  HISTORICAL  SKETCH  OF  THE  PTOMAINES. 

Definition. —  A  ptomaiue  is  a  chemical  compound 
which  is  basic  in  its  character,  and  which  is  formed  during 
the  putrefaction  of  organic  matter.  The  name  was  sug- 
gested by  Selmi,  and  is  derived  from  the  Greek  word 
-rCiiia  (cadaver).  On  account  of  their  Ijasic  properties,  in 
which  they  resemble  the  vegetable  alkaloids,  ptomaines 
may  be  called  putrefactive  alkaloids.  They  have  been 
called  animal  alkaloids,  but  this  is  a  misnomer,  because 
some  ptomaines  are  formed  by  the  putrefaction  of  vegetable 
matter,  as  will  be  shown  farther  on.  While  some  of  the 
ptomaines  are  highly  poisonous,  this  is  not  an  essential 
property,  for  others  are  wholly  inert.  Indeed,  the  greater 
number  of  those  which  have  been  isolated  up  to  the  present 
time  are  not  poisonous.  On  the  other  hand,  all  poisonous 
substances  formed  during  putrefaction  are  not  ptomaines. 
Thus  phenol  and  hydrogen  sulphide  are  poisonous  products 
of  putrefaction,  but  are  not  ptomaines. 

All  ptomaines  contain  nitrogen  as  an  essential  part  of 
their  basic  character.  In  this,  also,  they  resemble  the  vege- 
table alkaloids.  Some  of  them  contain  oxygen,  while 
others  do  not.  The  latter  correspond  to  the  volatile  vege- 
table alkaloids,  nicotine,  and  couiine,  and  the  former  corre- 
spond to  the  fixed  alkaloids. 

Since  all  putrefaction  is  due  to  the  action  of  bacteria,  it 
follows  that  all  ptomaines  result  from  the  growth  of  these 
microorganisms.     The  kind  of  ptomaine  formed  will  de- 


16  PTOMAINES. 

peud  upoD  the  individual  bacterium  engaged  in  its  produc- 
tion, the  nature  of  the  material  being  acted  npon  by  the 
bacterium,  and  the  conditions  under  which  the  putrefaction 
goes  on,  such  as  the  temperature,  amount  of  oxygen  present, 
the  electrical  conditions  existing,  and  the  duration  of  the 
process.  Only  the  bacillus  of  typhoid  fever  (Ebjceth's 
bacillus),  so  far  as  is  known  at  least,  can  produce  the 
ptomaine  typhotoxine,  and  the  special  bacterium  of  tetanus 
seems  to  be  necessary  in  order  to  produce  tetanine,  a 
ptomaine  which,  when  injected  under  the  skin  of  the  animal, 
causes  tetanic  convulsions.  Brieger  found  that,  althouo-h 
the  typhoid  bacillus  grew  well  in  solutions  of  peptone,  it 
did  not  produce  any  ptomaine;  while  from  cultures  of  the 
same  bacillus  in  beef-tea  he  obtained  a  poisonous  alkaloid. 
FiTZ  found  that  whilst  the  bacillus  butyricus  produces  by 
its  action  on  carbohydrates  butyric  acid,  in  glycerine  it 
produces  propylic  alcohol,  and  Moein  has  found  amyl 
alcohol  among  the  j)roducts  of  the  action  of  this  germ. 
Brown  has  shown  that  Avhile  the  mycoderma  aceti  converts 
ethylic  alcohol  into  acetic  acid,  it  converts  propylic  alcohol 
into  propionic  acid,  and  is  without  effect  upon  methylic 
alcohol,  primary  isobutylic  alcohol,  and  amylic  alcohol. 
Some  bacteria  Avill  not  multiply  below  a  given  temperature. 
Thus,  the  bacillus  butyricus  will  not  grow  at  a  temperature 
below  24°.^  The  lower  temperature  does  not  destroy  the 
organism,  but  it  lies  dormant  until  the  conditions  are  more 
favorable  for  its  growth.  Pasteur  divided  the  bacteria 
into  two  classes,  the  aerobic  and  the  anaerobic.  As  the  name 
implies,  the  former  grow  and  thrive  in  the  presence  of  air, 
while  the  latter  find  their  conditions  of  life  imj)roved  by  the 

1  All  temperatures  given  iii  this  work  are  Ceutigrade  unless  otherwise 
specified. 


DEFINITION.  17 

exclusiou  of  air.  Therefore,  different  ptomaines  will  be 
formed  in  decomposins;  matter  feeely  exposed  to  the  air,  and 
in  that  which  is  buried  beneath  the  soil  or  from  which  the 
air  is  laro-ely  excluded.  Even  Avhen  the  same  ferment  is 
present,  the  products  of  the  putrefaction  will  vary,  within 
certain  limits,  according  to  the  extent  to  which  the  putre- 
fyino-  material  is  supplied  with  air.  The  kind  of  ptomaine 
found  in  a  oiven  putrid  substance  will  depend  also  upon 
the  stage  of  the  putrefaction.  Ptomaines  are  transition 
products  in  the  process  of  putrefaction.  They  are  temporary 
forms  through  which  matter  passes  while  it  is  being  trans- 
formed, by  the  activity  of  bacterial  life,  from  the  organic 
to  the  inorganic  state.  Complex  organic  substances,  as 
muscle  and  brain,  are  broken  up  into  less  complex  mole- 
cules, and  so  the  process  of  chemical  division  goes  on  until 
the  simple  and  well-known  final  products,  carbonic  acid  gas, 
ammonia,  and  water,  result ;  but  the  variety  of  combina- 
tions into  which  an  individual  atom  of  carbon  may  enter 
during  this  long  series  of  changes  is  almost  unlimited,  and 
with  each  change  in  combination  there  is  more  or  less  change 
in  nature.  In  one  combination  the  atom  of  carbon  may 
exist  as  a  constituent  of  a  highly  poisonous  substance, 
while  the  next  combination  into  which  it  enters  may  be 
wholly  inert. 

It  was  formerly  supposed  that  putrefaction  was  simply 
oxidation,  but  tlie  researches  of  Pasteur  and  others  have 
demonstrated  the  fact  that  countless  myriads  of  minute 
organisms  are  engaged  constantly  in  transforming  matter 
from  the  organic  to  the  inorganic  form.  Lock  up  the  bit 
of  flesh  so  that  these  little  workers  cannot  reach  it,  and  it 
will  remain  unchanged  indefinitely. 

It  may  be  asked  if  any  of  the  changes  occurring  during 
putrefaction  are  to  be  regarded  as  purely  chemical.   AVithout 

2* 


18  PTOMAINES. 

doubt,  many  of  the  .secondary  products  of  putrefaction 
arise  from  reactions  between  antecedent  and  more  complex 
products,  or  by  the  action  of  oxygen,  water,  and  reducing 
agents  upon  primary  products.  Ptomaines  formed  in  this 
way  may  be  regarded  as  the  indirect  results  of  bacterial 
life. 

Historical  Sketch. — It  must  have  been  known  to 
primitive  man  that  the  eating  of  putrid  flesh  was  liable  to 
affect  the  health  more  or  less  seriously;  and  when  he  began 
his  endeavors  to  preserve  his  food  for  further  use,  instances 
of  poisoning  from  putrefaction  must  have  multiplied. 
However,  the  distinguished  physiologist  A.lbert  von 
Haller  seem!^  to  have  been  the  first  to  make  any  scientific 
experiments  concerning  the  effects  of  putrid  matter  upon 
animals.  He  injected  aqueous  extracts  of  putrid  material 
into  the  veins  of  animals  and  found  that  death  resulted. 
Later  in  the  eighteenth  century,  Morand  gave  an  account 
of  the  symptoms  induced  by  eating  poisonous  meat. 
In  the  early  part  of  the  present  century  (1808  to  1814), 
Gaspard  carried  on  similar  experiments.  He  used  as 
material  the  putrid  flesh  of  both  carnivorous  and  herbiv- 
orous animals.  With  these  he  induced  marked  nervous 
disturbances,  as  stiffness  of  the  limbs,  opisthotonos,  and 
tetanus.  Gaspard  concluded  from  the  symptoms  that  the 
poisonous  effects  were  not  due  to  carbonic  acid  gas  or 
hydrogen  sulphide,  but  thought  it  possible  that  ammonia 
might  have  part  in  their  production.  In  1820,  Kerner 
published  his  first  essay  on  poisonous  sausage,  which  was 
followed  by  a  second  in  1822.  At  first  he  thought  that  the 
poisonous  properties  were  due  to  a  fatty  acid,  similar  to  the 
sebacic  of  Thenard,  and  which  originated  during  putre- 
faction.    Later  he  modified  these  views,  and  believed  the 


HISTORICAL    SKETCH,  19 

poison  to  be  a  ooiupouiul  consistin*;'  of  the  sebacie  acid  and 
a  volatile  principle.  This  may  be  rcj^arded  as  the  first 
suo;gestion  as  to  the  probability  of  the  development  of  a 
poisonous  substance  with  basic  properties  in  decom])osing 
matter.  In  1822,  Duprh  observed  a  peculiar  disease 
among  the  soldiers  under  his  care,  who,  during  the  very 
warm  and  dry  summer  of  that  year,  were  compelled  to 
drink  very  foul  water.  Later,  Magendie,  induced  by  the 
investigations  of  Gaspard  and  the  observations  of  DuprI^:, 
made  many  experiments,  in  which  dogs  and  other  animals 
were  confined  over  vessels  containing  putrid  animal  matter 
and  compelled  constantly  to  breathe  the  emanations  there- 
from. The  effects  varied  markedly  with  the  species  of 
animal  and  the  nature  of  the  putrid  material,  but  in  some 
instances  symptoms  were  induced  which  resembled  closely 
those  of  typhoid  fever  in  man,  Leuret  directed  his 
attention  to  the  chemical  changes  produced  in  blood  by 
putrefaction,  but  accomplished  nothing  of  special  value, 
DupUY  injected  putrid  material  into  the  jugular  vein  of  a 
horse,  and  with  Trousseau  studied  alterations  produced 
in  the  blood  by  these  injections. 

During  the  third  decade  of  the  present  century  there 
were  many  investigators  in  addition  to  those  mentioned 
above,  who  endeavored  to  ascertain  the  active  agent  in 
poisonous  foods.  Dann,  Weiss,  Buchner,  Schumann, 
Cadet  de  Gassicourt,  and  Orfila  studied  poisonous 
sausage,  but  made  uo  advance  upon  the  work  done  by 
Kerner.  Henneman,  HiiNNEFELD,  Westrumb,  and 
Serturner  made  contributions  concerning  poisonous 
cheese,  but  all  believed  the  caseic  acid  of  Kerner  to  be 
the  poisonous  principle. 

In  1850,  Schmidt,  of  Dorpat,  made  some  investiga- 
tions on  the  decompositio)!  products  and  volatile  substances 


20  PTOMAINES. 

found  in  cholera  stools ;  and,  two  years  later,  Meyer,  of 
Berlin,  injected  the  blood  and  stools  of  cholera  patients  into 
lower  animals.  In  1853,  Stick  made  an  important  con- 
tribution on  the  effects  of  acute  poisoning  with  putrid 
material.  He  ascertained  that,  when  given  in  sufficient 
quantity,  putrid  matter  produces  an  intestinal  catarrh,  with 
choleraic  stools.  Nervous  symptoms,  trembling,  unsteady 
gait,  and  finally  convulsions,  were  also  observed.  Stick 
made  careful  post-mortem  examinations,  and  was  unable  to 
find  any  characteristic  or  important  lesion.  Theoretically, 
he  concluded  that  the  putrid  material  contained  a  ferment 
which  produced  rapid  decomposition  of  the  blood. 

In  1856,  Panum  published  a  most  important  contribu- 
tion to  the  kuQwledge  of  the  nature  of  the  poison  present 
in  putrid  flesh.  He  first  demonstrated  positively  the  chem- 
ical character  of  the  poison,  inasmuch  as  he  showed  that 
the  aqueous  extract  of  the  putrid  material  retained  its 
poisonous  properties  after  treatment  w^hich  would  insure 
the  destruction  of  all  organisms.  His  conclusions  were  as 
follows : 

(1)  "The  putrid  poison  contained  in  the  decomposed 
flesh  of  the  dog,  and  which  is  obtained  by  extraction  with 
distilled  water  and  repeated  filtration,  is  not  volatile,  but 
fixed.  It  does  not  pass  over  on  distillation,  but  remains  in 
the  retort." 

(2)  "The  putrid  poison  is  not  destroyed  by  boiling,  nor 
by  evaporation.  It  preserves  its  poisonous  properties  even 
after  the  boiling  has  been  continued  for  eleven  hours,  and 
after  the  evaporation  has  been  carried  to  complete  desicca- 
tion at  100°." 

(3)  "  The  putrid  poison  is  insoluble  in  absolute  alcohol, 
but  is  soluble  in  water,  and  is  contained  in  the  aqueous 

extract  which  is  formed  by  treating  with  distilled  water 


HISTORICAL    SKETCH.  21 

the  putrid  material  which  has  previously  beeu    dried  by 
heat  and  washed  with  alcohol." 

(4)  "The  albuminoid  substances  which  frequently  are 
found  in  putrid  fluids  are  net  in  themselves  poisonous  only 
so  far  as  they  contain  the  putrid  poison  fixed  and  condensed 
upon  their  surfaces,  from  Avliich  it  can  be  removed  by 
repeated  and  careful  washing-." 

(5)  "  The  intensity  of  the  putrid  poison  is  comparable  to 
that  of  the  venom  of  serpents,  of  curare,  and  of  certain 
vegetable  alkaloids,  iuasnuich  as  0.012  of  a  o-ram  of  the 
poison,  obtained  by  extracting  with  distilled  water  putrid 
material  which  had  been  previously  boiled  for  a  long  time, 
dried  at  100°  and  submitted  to  the  action  of  absolute 
alcohol,  was  sufficient  almost  to  kill  a  small  dog." 

Panum  made  intravenous  injections  with  this  poison,  and 
with  ammonium  carbonate,  ammonium  butyrate,  ammo- 
nium valerianate,  tyrosine,  and  leucine,  and  found  that  the 
symptoms  induced  by  the  putrid  poison  differed  from  those 
caused  by  the  other  agents.  Moreover,  he  found  the  symp- 
toms to  differ  from  those  of  typhoid  fever,  cholera,  pysemia, 
anthrax,  and  sausage  poisoning.  He  was  also  in  doubt  as 
to  whether  the  poison  acted  directly  upon  the  nervous 
system,  or  whether  it  acted  as  a  ferment  upon  the  blood, 
causing  decomposition,  the  products  of  which  affected  the 
nerve-centres;  but  he  was  sure  that  it  could  not  correspond 
to  the  ordinary  ferments,  inasmuch  as  it  was  not  decom- 
posed by  prolonged  boiling  nor  by  treatment  with  absolute 
alcohol.  Certainly,  the  putrid  poison  could  not  consist  of 
a  living  organism. 

The  symptoms  observed  by  Panum  varied  greatly  with 
the  quantity  of  the  poison  used  and  the  strength  of  the 
animal.  After  the  intravenous  injection  of  large  doses, 
death  followed  in  a  very  short  time.     In  these  cases  there 


^ 


22  PTOMAINES. 

were  violent  cramps,  and  involuntary  evacuations  of  the 
urine  and  faeces ;  the  respirations  were  labored,  the  pallor 
was  marked,  sometimes  followed  by  cyanosis,  the  pulse 
feeble,  the  pupils  widely  dilated,  and  the  eyes  projecting. 
In  these  cases  the  autopsy  did  not  reveal  any  lesion,  save 
that  the  blood  was  dark,  imperfectly  coagulated  and  slightly 
infiltrated  through  the  tissue.  Post-mortem  putrefaction 
came  on  with  extraordinary  rapidity. 

When  smaller  doses. or  more  vigorous  animals  were  used, 
the  symptoms  did  not  appear  before  from  a  quarter  of  an 
hour  to  two  hours,  and  sometimes  even  later.  In  these 
cases  the  symptoms  were  less  violent,  and  the  animal  gen- 
erally recovered.  In  all  instances,  however,  the  disturb- 
ances were  more  or  less  marked. 

In  addition  to  the  "  putrid  poison,"  Panum  obtained  a 
narcotic  substance,  the  two  being  separated  by  the  solubility 
of  the  narcotic  in  alcohol.  The  alcoholic  extract  was  evap- 
orated to  dryness,  the  residue  dissolved  in  water  and  injected 
into  the  jugular  vein  of  a  dog.  The  animal  fell  into  a  deep 
sleep,  which  remained  unbroken  for  twenty-four  hours, 
when  it  awoke  apparently  in  perfect  health. 

Panum's  first  contributions,  which  were  published  in 
Danish,  did  not  attract  the  attention  which  they  deserved, 
until  after  the  lapse  of  several  years.  ISTow,  however,  their 
importance  is  fully  appreciated,  and  the  distinguished  inves- 
tigator lived  to  receive  the  credit  and  honor  due  him. 

Weber  in  1864,  and  Hemmer  and  Schwexxinger 
in  1866,  confirmed  the  results  obtained  by  Paxum  ;  and 
ScHWEXNi^y^GER  announced  that  in  the  various  stages  of 
putrefaction  different  products  are  formed,  and  that  these 
vary  in  their  effects  upon  animals.  In  1866,  Bence 
Jones  and  Dupre  obtained  from  the  liver  a  substance 
which  in  solutions  of  dilute  sulphuric  acid  gives  the  blue 


HISTORICAL    SKETCH.  23 

fluorescence  observed  iu  similar  solutions  of  quinine.  To 
this  substance  they  gave  the  name  "  animal  chinoidine." 
Subsequently,  the  same  investigators  found  this  substance 
iu  all  organs  and  tissues  of  the  body,  but  most  abundantly 
iu  the  nerves.  Its  feebly  acid  solutions  give  precipitates 
with  iodine,  potassio-mercuric  iodide,  phosphomolybdic 
acid,  gold  chloride,  and  platinum  chloride.  From  three 
pounds  of  sheep's  liver,  they  obtained  three  grams  of  a 
solution  in  which,  after  slight  acidulation  with  sulphuric 
acid,  the  intensity  of  the  fluorescence  was  about  the  same 
as  that  of  a  similarly  acidulated  solution  of  quinine  sulphate 
which  contained  0.2  gram  of  quinine  per  litre.  Still  later, 
this  base  was  obtained  by  Marino-Zuco. 

In  1868,  Bergmann  and  Schmiedeberg  separated, 
first  from  putrid  yeast,  and  subsequently  from  decomposed 
blood,  in  the  form  of  a  sulphate,  a  poisonous  substance 
which  they  named  sepsine.  The  sulphate  of  sepsine  forms 
in  needle-shaped  crystals.  Small  doses  (0.01  gram)  of 
this  substance  were  dissolved  in  water  and  injected  into 
the  veins  of  two  dogs.  In  a  short  time  it  produced 
vomiting,  and  later  diarrhoea,  which,  in  one  of  the  animals, 
after  a  time,  became  bloody.  Post-mortem  examination 
showed,  in  the  stomach  and  intestines,  bloody  ecchymoses. 
It  was  now  believed  that  the  "  putrid  poison  "  of  Panum 
had  been  isolated,  and  that  it  was  identical  with  sepsine, 
but  further  investigations  showed  that  this  was  not  true. 
There  are  marked  differences  iu  their  effects  upon  animals, 
and  sepsine  has  not  been  found  to  be  generally  present  in 
putrid  material.  It  is  only  rarely  found  in  blood,  and  the 
closest  search  has  failed  to  show  its  presence  in  pus.  Berg- 
MANN,  following  the  same  method  which  he  had  used  iu 
extracting  this  poison  from  yeast,  has  been  uuable  to  obtain 
it   from  other   putrid    material.     Moreover,  he   was   not 


24  PTOMAINES. 

always  successful  in  obtaining  the  poison  from  yeast.  Sep- 
sine  was  not  obtained  in  quantity  sufficient  to  serve  for  an 
ultimate  analysis,  hence,  its  composition  remains  unknown. 

In  1869  ZtJLZER  and  Sonnenschein  prepared  from 
decomposed  meat  extracts  a  nitrogenous  base,  which  in  its 
chemical  reactions  and  physiological  effects  resembled  atro- 
pine and  hyoscyamine.  When  injected  under  the  skin  of 
animals  it  produced  dilatation  of  the  pupils,  paralysis  of 
the  muscles  of  the  intestines,  and  acceleration  of  the  heart- 
beat; but  it  is  uncertain  and  inconstant  in  its  action.  This 
probably  results  from  rapid  decomposition  taking  place  in 
it,  or  to  variations  in  its  composition  at  different  stages  of 
putrefaction.  This  substance  has  also  been  obtained  from 
the  bodies  of, those  who  have  died  from  typhoid  fever,  and 
it  may  be  possible  that  the  belladonna-like  delirium  which 
frequently  characterizes  the  later  stages  of  this  disease  is 
due  to  the  ante-mortem  generation  of  this  poison  within 
the  body. 

Since  1870  many  chemists  have  been  engaged  in  making 
investigations  on  the  products  of  putrefaction.  We  can 
only  mention  a  few  names  at  present,  while  others  will  be 
referred  to  subsequently  in  discussing  the  individual  pto- 
maines. 

First  of  all  stands  the  Italian  Selmi,  who  suggested  the 
name  ptomaine,  and  whose  researches  furnished  us  with 
much  information  of  value,  and,  what  is  probably  of  more 
importance,  gave  an  impetus  to  the  study  of  the  chemistry 
of  putrefaction,  which  has  already  been  productive  of  much 
good  and  gives  promise  of  much  more  in  the  future.  Sei.mi 
showed  that  ptomaines  could  be  obtained  (1)  by  extracting 
acidified  solutions  of  putrid  material  with  ether ;  (2)  by 
extracting  alkaline  solutions  with  ether ;  (3)  by  extracting 
alkaline  solutions  with  chloroform ;  (4)  by  extracting  with 


HISTORICAL    SKETCH.  25 

amy  lie  alcohol;  and  (5)  that  tliere  yet  remaiued  in  the  solu- 
tions of  putrid  matter  ptomaines  which  were  not  extracted 
by  any  of  the  above-mentioned  reagents.  In  this  way  he 
gave  some  idea  of  the  great  number  of  alkaloidal  bodies 
which  might  be  formed  among  the  products  of  putrefaction, 
and  the  promising  field  thus  discovered  and  outlined  was 
soon  occupied  l)y  a  busy  host  of  chemists.  In  the  second 
place,  he  demonstrated  the  fact  that  many  of  the  ptomaines 
give  reactions  similar  to  those  given  by  the  vegetable  alka- 
loids. This  led  the  toxicologist  into  investigations,  the 
results  of  some  of  which  we  will  ascertain  further  on. 

Selmi,  however,  did  not  succeed  in  isolating  completely 
a  single  putrefactive  alkaloid.  All  his  work  was  done  with 
extracts.  He  remained  ignorant,  except  in  a  general  way, 
of  the  composition  of  these  bodies.  NE^x•KI,  in  1876, 
made  the  first  ultimate  analysis  and  determined  the  first 
formula  of  a  ptomaine.  This  was  an  isomer  of  collidine, 
which  will  be  described  later. 

RoESCH  and  Fassbendee,  in  a  case  of  suspected  poison- 
ing, obtained  by  the  Stas-Otto  method  a  liquid  which 
could  be  extracted  from  acid  as  well  as  alkaline  solutions 
by  ether,  and  which  gave  all  the  general  alkaloidal  reac- 
tions. They  were  unable  to  crystallize  either  extract  by 
taking  it  up  with  alcohol  and  evaporating.  The  colorless 
aqueous  solution  was  not  at  all  bitter  to  the  taste.  The 
precipitate  formed  with  phosphomolybdic  acid  dissolved  on 
the  application  of  heat,  giving  a  green  solution,  which 
became  blue  on  the  addition  of  ammonia.  They  believed 
that  this  substance  was  derived  from  the  liver,  since  fresh 
ox-liver,  treated  in  the  same  manner,  gave  them  an  alkaloid 
which  could  be  extracted  with  ether  from  acid  as  well  as 
from  alkaline  solutions.  Guxning  found  this  same  alka- 
loid in  liver-sausage  from  which  poisoning  had  occurred. 

3 


26  PTOMAINES. 

RoESCH  and  Fassbejstdee  state  that  while  in  some  of  its 
reactions  this  substance  resembles  digitaline,  it  is  distin- 
guished from  this  vegetable  alkaloid  by  the  failure  of  the 
ptomaine  to  give  the  characteristic  bitter  taste. 

ScHWANEET,  whilst  examining  the  decomposing  intes- 
tines, liver,  and  spleen  of  a  child  which  had  died  suddenly, 
perceived  a  peculiar  odor  and  obtained  by  the  Stas-Otto 
method  (ether  extract  from  an  alkaline  solution)  small 
quantities  of  a  base,  which  was  distinguished  from  nicotine 
and  coniine  by  its  greater  volatility  and  its  peculiar  odor. 
He  supposed  that  this  substance  was  produced  by  decom- 
position, and,  in  order  to  ascertain  the  truth  of  his  suppo- 
sition, he  took  the  organs  of  a  cadaver  that  had  lain  for 
sixteen  days  at  a  temperature  of  30°,  and  was  well 
decomposed.  These  were  treated  with  tartaric  acid  and 
alcohol.  The  acid  solution  was  first  extracted  with  ether, 
and  yielded  no  result,  it  was  then  rendered  alkaline  and  ex- 
tracted with  ether.  The  latter  extract  gave,  on  evaporation, 
the  same  substance  which  he  had  found  in  the  organs  of  the 
child.  The  residue  was  a  yellowish  oil,  having  an  odor 
somewhat  similar  to  propylamine.  It  was  repulsive,  but 
not  bitter  to  the  taste,  and  alkaline  in  reaction.  On  the 
addition  of  hydrochloric  acid,  it  crystallized  in  white  needles, 
which  were  freely  soluble  in  water,  but  soluble  with  diffi- 
culty in  alcohol.  On  the  addition  of  ammonium  hydrate 
to  this  crystalline  substance,  a  white  vapor  of  unpleasant 
odor  was  given  off.  The  crystals  dissolved  in  sulphuric  acid, 
forming  a  solution  which  was  at  first  colorless,  but  which 
gradually  became  dirty  brownish -yellow,  and  grayish- 
brown  on  the  application  of  heat.  On  being  warmed  with 
sodium  molybdate,  a  splendid  blue  color,  becoming  gradu- 
ally gray,  was  produced.  Potassium  bichromate  and  sul- 
phuric acid  gave  a  reddish-brown,  then  a  grass-green  color. 


HISTORICAL    SKETCH.  27 

Nitric  acid  gave  a  yellow  color,  A  tartaric  acid  solution 
of  the  crystals  produced,  on  the  addition  of  platinum  chlo- 
ride, a  dirty  yellow  precipitate  of  small  six-sided  stars, 
which  contained  31.55  per  cent,  of  platinum.  Gold  chlo- 
ride gave  a  pale  yellow,  amorphous  precipitate ;  mercuric 
chloride  yielded  white  crystals ;  potassio-mercuric  iodide  a 
dirty  white  precipitate;  and  potassio-cadmic  iodide  yielded 
no  result.  Tannic  acid  produced  only  a  turbidity.  Sodium 
phosphomolybdate  gave  a  yellow,  flocculent  precipitate, 
which  became  blue  on  the  addition  of  ammonium  hydrate. 
This  base  has  a  slight  reducing  power,  and  in  this  it 
resembles  a  substance  obtained  by  Selmi,  but  it  differs 
from  Selmi's  extract  inasmuch  as  it  does  not  give  a  violet 
coloration  on  being  warmed  with  sulphuric  acid.  In  its 
amorphous  character,  its  behavior  to  the  general  alkaloidal 
reagents,  and  its  lack  of  bitter  taste,  it  resembles  the  base 
obtained  by  Rorsch  and  Fassbender,  but,  unlike  that 
alkaloid,  it  is  extractable  from  alkaline  solutions  only. 

Selmi,  in  commenting  upon  the  base  studied  by  Rorsch 
and  Fassbender,  Schwanert,  and  himself,  believing 
that  all  were  dealing  with  the  same  body,  states  that  it 
does  not  contain  phosphorus,  and  that  it  is  separated  with 
extreme  difficulty  fi-om  the  vegetable  alkaloids. 

Liebermanx,  in  examining  the  somewhat  decomposed 
stomach  and  intestines  in  a  case  of  suspected  poisoning, 
found  an  alkaloidal  body  which  was  unlike  that  studied  by 
the  chemists  mentioned  above,  inasmuch  as  it  was  not  vola- 
tile. The  Stas-Otto  method  was  employed.  The  ether 
extract  from  alkaline  solution  left,  on  evaporation,  a  brown- 
ish, resinous  mass,  which  dissolved  in  water  to  a  turbid 
solution,  the  cloudiness  increasing  on  heating.  This  reac- 
tion agrees  with  coniine,  but  the  odor  differed  from  that  of 


28  PTOMAINES. 

the  vegetable  alkaloid.      The  aqueous,  strongly  alkaline 
solution  gave  the  following  reactions  : 

(1)  With  tannic  acid,  a  white  precipitate. 

(2)  With  potassium  iodide,  a  yellowish-brown,  turning 
to  dark  brown  precipitate. 

(3)  With  chlorine  water,  a  marked  white  cloudiness. 

(4)  With  phosphomolybdic  acid,  a  yellow  precipitate. 

(5)  With  potassio-mercuric  iodide,  a  white  precipitate. 

(6)  With  mercuric  chloride,  a  white  cloudiness. 

(7)  With  concentrated  sulphuric  acid,  after  a  while,  a 
reddish- violet  coloration. 

(8)  With  concentrated  nitric  acid,  after  evaporation,  a 
yellowish  spot. 

These  reactions  exclude  all  vegetable  alkaloids  save 
coniine.  The  putrefactive  alkaloid  does  not  distil  when 
heated  on  the  oil-bath  to  200°,  while  coniine  distils  at 
135°.  The  former  is  with  certainty  distinguished  from 
coniine  by  its  non-poisonous  properties. 

This  substance  is  extracted  by  ether  from  acid,  as  well 
as  from  alkaline  solutions.  The  yellow,  oily  drops  ob- 
tained after  the  evaporation  of  the  ether  are  soluble  in 
alcohol.     The  taste  is  slightly  burning. 

Selmi  obtained  from  both  putrefying  and  fresh  intes- 
tines a  substance  which  gave  the  general  alkaloidal  reac- 
tions with  potassium  iodide,  gold  chloride,  platinum  chlo- 
ride, potassio-mercuric  iodide,  and  phosphomolybdic  acid. 
It  has  strong  reducing  power,  and  when  warmed  with 
sulphuric  acid  gives  a  violet  coloration.  These  reactions 
are  not  due  to  leucine,  tyrosine,  creatine,  or  creatinine. 
This  is  the  substance  which,  as  has  been  stated,  Selmi  con- 
sidered identical  with  that  observed  by  Roesch  and  Fass- 
BENDER  and  ScHWANEET.  The  minor  differences  observed 
by  the  different  chemists  may  have  been  due  to  the  varying 


HISTORICAL    SKETCH.  29 

degrees  of  purity  in  which  tlic  substance  was  obtained  by 
them. 

From  human  bodies  which  had  been  dead  from  one  to 
ten  months,  Sp:LMr  removed  many  alkaline  bases.  From 
an  ether  solution  of  a  number  of  these,  one  was  removed 
by  treatment  with  carbonic  acid  gas.  One  base  which  was 
insoluble  in  ether,  but  readily  soluble  in  amylic  alcohol, 
was  found  to  be  a  violent  poison,  producing  in  rabbits, 
tetanus,  marked  dilatation  of  the  pupils,  paralysis,  and 
death. 

Parts  of  a  human  body  preserved  in  alcohol  were  found 
by  Selmi  to  yield  an  easily  volatile,  phosphorus-containing 
substance,  which  is  soluble  in  ether  and  carbon  disulphide, 
and  gives  a  brown  precipitate  with  silver  nitrate.  It  is 
not  the  phosphide  of  hydrogen,  A  similar  substance  is 
produced  by  the  slow  decomposition  of  the  yolks  of  eggs. 
With  potassium  hydrate  it  gives  off  ammonia  and  yields  a 
substance  having  an  intense  coniine  odor.  It  is  volatile 
and  reduces  phosphomolybdic  acid. 

Selmi  also  obtained  from  decomposing  egg-albumen  a 
body,  whose  chloride  forms  in  needles,  and  which  has  a 
curare-like  action  on  frogs.  From  one  arsenical  body  which 
had  been  buried  for  fourteen  days,  he  obtained,  by  extract- 
ing from  an  alkaline  (made  alkaline  with  baryta)  solution 
with  ether,  a  substance  which  formed  in  needles  and  which 
gave  crystalline  salts  with  acids.  With  sulphuric  acid  it 
gave  a  red  color;  with  iodic  acid  and  sulphuric  acid  it 
liberated  free  iodine  and  gave  a  violet  coloration  ;  with 
nitric  acid  it  gave  a  beautiful  yellow,  which  deepened  on 
the  addition  of  caustic  potash.  Platinum  chloride  gave  no 
precipitate  save  in  highly  concentrated  solutions.  From  a 
second  arsenical  body,  Selmi  obtained  by  the  same  method 
a  substance  which  gave,  with  tannic  acid,  a  white  precipi- 

3* 


30  PTOMAINES. 

tate ;  with  iodine  in  hydriodic  acid  a  kermes-brown  ;  with 
gold  chloride  a  yellow,  which  was  soon  reduced  ;  with 
mercuric  chloride  a  white ;  M'ith  picric  acid  a  yellow, 
which  gradually  formed  in  crystalline  tablets.  This  sub- 
stance did  not  contain  any  arsenic,  but  was  highly  poi- 
sonous. From  the  stomach  of  a  hog,  which  had  been  pre- 
served in  a  solution  of  arsenious  acid,  Selmi  separated  an 
arsenical  organic  base.  The  fluid  was  distilled  in  a  current 
of  hydrogen.  The  distillate,  which  was  found  to  be  strongly 
alkaline,  was  neutralized  with  hydrochloric  acid  and  evapo- 
rated to  dryness,  when  cross-shaped  crystals,  giving  an  odor 
similar  to  that  of  trimethylaniine,  were  obtained.  This  sub- 
stance was  found  by  CiACCiA  to  be  highly  poisonous,  pro- 
ducing strychnia-like  symptoms.  With  iodine  in  hydriodic 
acid  it  is  said  to  give  a  gray,  crystalline  precipitate. 

From  the  liquid  which  remained  in  the  retort,  a  non- 
volatile arsenical  ptomaine  was  extracted  with  ether.  An 
ac^ueous  solution  of  this  gave  with  tannic  acid  a  slowly 
forming,  yellowish  precipitate,  and  similarly  colored  pre- 
cipitates with  iodine  in  hydriodic  acid,  platinum  chloride, 
auric  chloride,  mercuric  chloride,  potassio-mercuric  iodide, 
potassio-bismuthic  iodide,  picric  acid,  and  potassium  bi- 
chromate. The  physiological  action  of  this  substance  as 
demonstrated  on  frogs  was  unlike  that  of  the  arsines,  but 
consisted  of  torpor  and  paralysis. 

MoPviGGiA  and  Battlstixi  experimented  with  alkaloids 
obtained  from  decomposing  bodies  upon  guinea-pigs  and 
frogs,  but  did  not  attempt  their  isolation  because  of  the 
rapid  decomposition  which  they  undergo  when  exposed  to 
the  air  and  by  which  they  lose  their  poisonous  properties. 
These  alkaloids  they  found  to  be  easily  soluble  in  amylic 
alcohol,  less  soluble  in  ether. 

In  1871  LoiiBROSO  showed  that  the  extract  from  mouldy 


HISTORICAL    SKETCH.  31 

corn-meal  produced  tetanic  convulsions  in  animals.  This 
threw  some  light  upon  the  cases  of  sporadic  illness  which 
had  long  been  known  to  occur  among  the  peasants  of  Lom- 
bardy,  who  eat  fermented  and  mouldy  corn-meal.  In  187G 
Brugnatelli  and  Zenoni  obtained  by  the  Stas-Otto 
method  from  this  mouldy  meal  an  alkaloidal  substance 
which  was  white,  non-crystalline,  unstable,  and  insoluble 
in  water,  but  readily  soluble  in  alcohol  and  ether.  With 
sulphuric  acid  and  bichromate  of  potassium  it  yields  a 
color  reaction  very  similar  to  that  of  strychnine. 

The  action  of  the  ether  extracts  from  decomposed  brain 
resembles  that  of  curare,  but  is  less  marked  and  more 
transitory.  The  beats  of  the  frog's  heart  were  decreased  in 
number  and  strengthened  in  force;  the  nerves  and  the 
muscles  lost  their  irritability,  and  the  animal  passed  into 
a  condition  of  complete  torpor.  The  pupils  were  dilated. 
GuARESCHi  and  Mosso,  using  the  Stas-Otto  method, 
obtained  from  human  brains  which  had  been  allowed  to 
decompose  at  a  temperature  of  from  10°  to  15°  for  from 
one  to  two  months,  both  volatile  and  non-volatile  bases. 
Among  the  former  only  ammonia  and  trimethylamine 
were  in  sufficient  quantity  for  identification.  With  these, 
however,  were  minute  traces  of  ptomaines. 

They  obtained  non-volatile  bases  from  both  acid  and 
alkaline  solutions.  From  the  former,  they  separated  a  sub- 
stance which  gave  precipitates  with  gold  chloride,  jihospho- 
tungstic  acid,  phosphomolybdic  acid,  Mayer's  reagent, 
palladium  chloride,  picric  acid,  iodine  in  potassium  iodide, 
and  slightly  with  tannic  acid.  This  substance  was  not 
precipitated  with  platinum  or  mercury. 

From  the  alkaline  extract  there  was  obtained  a  substance 
which  in  dilute  hydrochloric  acid  solutions  gave  with  gold 
chloride  a  heavy  yellow  precipitate  with    reduction,  also 


32  PTOMAINES. 

precipitates  with  phosphomolybclic  acid,  platinum  chloride, 
Mayer's  reagent^  picric  acid,  phosphotungstic  acid, 
Maeme's  reagent,  iodine  in  potassium  iodide,  tannin,  bi- 
chromate of  potassium,  palladium  chloride,  and  mercuric 
chloride.  It  reduces  ferric  salts.  From  decomposed  fibrin 
the  same  investigators  obtained  one  well-defined  ptomaine. 
Analyses  of  the  platinum  compound  of  this  substance  gave 
the  formula  Cn,Hj-lSr.  This  substance  will  be  discussed  in 
a  future  chapter. 

From  fresh  brain  substance  they  separated  ammonia, 
trimethylamine,  and  an  undetermined  base.  These,  how- 
ever, are  not  to  be  regarded  as  products  of  putrefaction, 
but  as  resulting  from  the  action  of  the  reagents  ujdou  the 
brain  substance.  The  trimethylamine  probably  arises  from 
the  splitting  up  of  lecithin,  while  the  undetermined  base 
is  most  likely  choline,  which  also  results  from  the  breaking 
up  of  the  lecithin  molecule. 

They  also  show  that  when  Dragendoeff's  method  is 
used  basic  substances  can  be  obtained  from  fresh  meat,  and 
these  are  shown  to  be  produced  by  the  action  of  the  sul- 
phuric acid  on  the  flesh. 

To  Brieger,  of  Berlin,  is  due  the  credit  of  isolating 
and  determining  the  composition  of  a  number  of  ptomaines. 
From  putrid  flesh  he  obtained  neuridine,  CgHj^Ng,  and 
neurine,  C5HJ3NO.  The  former  is  inert,  while  the  latter  is 
poisonous.  From  decomposed  fish  he  separated  a  poisonous 
base,  C2H4  (NH2)2,  which  is  an  isomeride  of  ethylenediamine, 
muscarine,  C5H15NO3,  and  an  inert  substance,  C^Hj^NOg, 
gadiniue.  Rotten  cheese  yielded  neuridine  and  trimethyla- 
mine. Decomposed  glue  gave  neuridine,  dimethylamine, 
and  a  muscarine-like  base.  In  the  cadaver,  he  has  found 
in  difi^erent  stages  of  decomposition,  choline,  neuridine,  tri- 
methylamine, cadaverine,  C5Hj^N2j  putrescine,  C^H^g-^a;  ^^^ 


HISTORICAL    SKETCH.  33 

saprine,  C^Hi^N^.  These  are  all  inert.  After  fourteen 
(lays  of  decomposition  he  found  a  poisonous  substance, 
mydaleine.  From  a  cadaver  which  had  been  kept  at  from 
—  9°  to  +  5°  C.  for  four  months,  Brieger  obtained 
mydine,  CgHjjXO,  the  poisonous  substance  mydatoxine, 
CgHijXOo,  also  the  poison  methyl-guanidine.  From 
poisonous  mussel  he  separated  mytilotoxine,  CgHj^NOj. 
From  pure  cultures  of  the  typhoid  bacillus  of  Koch  and 
Eberth,  Brieger  obtained  a  poison,  typhotoxiue,  and, 
from  like  cultures  of  the  tetanus  germ  of  Rosenbach, 
tetanine.  All  of  these  bases  will  be  discussed  in  detail  in 
a  subsequent  chapter. 

Gautier  and  Etard  have  also  isolated  ptomaines  which 
will  be  described  later. 

In  1885,  Vaughax  succeeded  in  isolating  the  active 
agent  of  poisonous  cheese,  to  which  he  gave  the  name 
tyrotoxicon.  This  discovery  has  been  confirmed  by 
Newtox,  Wallace,  Sch.effer,  Staxton,  Firth, 
Ladd,  and  \yoLFF. 

NiCATi  and  Rietsch,  Koch,  and  others,  have  shown 
the  presence  of  a  poisonous  substance  in  cultures  of  the 
cholera  bacillus.  Salmox  and  Smith  have  done  the  same 
with  cultures  of  the  hog  cholera  germ  ;  Hoffa,  with  those 
of  the  anthrax  bacillus ;  and  Brieger  with  those  of  the 
tetanus  crerm. 


CHAPTER    II. 

FOODS  CONTAmmO  POISONOUS  PTOMAINES. 

Poisonous  Mussels. — Judging  from  the  symptoms 
produced,  there  seem  to  be  three  different  kinds  of  poisonous 
mussel.  In  one  class,  the  symptoms  resemble  those  of  a 
true  gastro-intestinal  irritant.  Fodere  reports  the  case  of 
a  sailor,  who,  after  eating  a  large  dish  of  mussels,  suffered 
from  nausea,  vomiting,  pain  in  the  stomach,  tenesmus,  and 
rapid  pulse.  After  death,  which  occurred  within  two  days, 
the  stomach  and  intestines  were  found  inflamed  and  filled 
with  a  tenacious  mucus.  Combe  and  others  also  report 
cases  of  the  choleraic  form  of  poisoning  from  mussel. 

However,  the  symptoms  which  most  frequently  manifest 
themselves  after  the  eating  of  poisonous  mussels  are  more 
purely  nervous.  A  sensation  of  heat  and  itching  appears 
usually  in  the  eyelids,  and  soon  involves  the  whole  face, 
and  perhaps  a  large  portion  of  the  body.  An  eruption, 
usually  called  nettle-rash,  though  it  may  be  papular  or 
vesicular,  covers  the  parts.  The  itching  is  most  annoying, 
and  may  be  accompanied  by  marked  swelling.  There 
follows  a  distressing  asthmatic  breathing,  which  is  relieved 
by  ether.  In  some  cases  reported  by  Mohring,  dyspnoea 
preceded  the  eruption,  the  patients  became  insensible,  the 
face  livid,  and  convulsive  movements  of  the  extremities 
were  noticed.  Burrow  reports  similar  cases  with  de- 
lirium, convulsions,  coma,  and  death  within  three  days. 

In  a  third  class  of  cases,  there  may  be  a  kind  of  intoxi- 


POISONOUS    MUSSELS.  35 

cation  resembling  somewhat  that  of  alcohol,  then  paralysis, 
coma,  and  death. 

In  1827,  Combe  observed  thirty  persons  poisoned,  two 
of  them  fatally,  with  mnssels.  He  describes  the  symptoms 
as  follows  :  "  None,  so  far  as  I  know,  complained  of  any- 
thing peculiar  in  the  smell  or  taste  of  the  animals,  and 
none  suffered  immediately  after  taking  them.  In  general, 
an  hour  or  two  elapsed,  sometimes  more;  and  the  bad 
effects  consisted  rather  in  uneasy  feelings  and  debility,  than 
in  any  distress  referable  to  the  stomach.  Some  children 
suffered  from  eating  only  two  or  three;  and  it  will  be  re- 
membered that  Robertson,  a  young  and  healthy  man,  only 
took  five  or  six.  In  two  or  three  hours  they  complained 
of  a  slio:ht  tension  at  the  stomach.  One  or  two  had 
cardialgia,  nausea,  and  vomiting ;  but  these  were  not 
general,  or  lasting  symptoms.  They  then  complained  of  a 
prickly  feeling  in  their  hands,  heat  and  constriction  of  the 
mouth  and  throat;  difficulty  of  swallowing  and  speaking 
freely;  numbness  about  the  mouth,  gradually  extending  to 
the  arms,  with  great  debility  of  the  limbs.  The  degree  of 
muscular  debility  varied  a  good  deal,  but  was  an  invariable 
symptom.  In  some  it  merely  prevented  them  from  walking 
firmly,  but  in  most  of  them  it  amounted  to  perfect  inability 
to  stand.  While  in  bed  they  could  move  their  limbs  with 
tolerable  freedom,  but  on  being  raised  to  the  perpendicular 
posture  they  felt  their  limbs  sink  under  them.  Some  com- 
plained of  a  bad,  coppery  taste  in  the  mouth,  but  in  general 
this  was  in  answer  to  what  lawyers  call^a  leading  question. 
There  was  slight  pain  of  the  abdomen,  increased  on  pres- 
sure, particularly  in  the  region  of  the  bladder,  which  organ 
suffered  variously  in  its  functions.  In  some  the  secretion 
of  urine  was  suspended,  in  others  it  was  free,  but  passed 
with  pain  and  great  effort.     The  action  of  the  heart  was 


36  PTOMAINES. 

feeble  ;  the  breathing  uualfected  ;  the  face  pale,  expressive 
of  much  anxiety ;  the  surface  rather  cold ;  the  mental 
faculties  unimpaired.  Unluckily,  the  two  fatal  cases  were 
not  seen  by  any  medical  person ;  and  we  are,  therefore, 
unable  to  state  minutely  the  train  of  symptoms.  We 
ascertained  that  the  woman,  in  whose  house  were  five  suf- 
ferers, went  away  as  in  a  gentle  sleep,  and  that  a  few 
moments  before  death  she  had  spoken  and  swallowed." 

The  woman  died  within  three  hours,  and  the  other  death 
was  that  of  a  watchman  who  was  found  dead  in  his  box 
six  or  seven  hours  after  he  had  eaten  the  mussels.  Post- 
mortem examination  in  these  showed  no  abnormality.  The 
stomach  contained  some  of  the  food  partially  digested. 

The  explorer  Vancouver  reports  four  cases  similar 
to  those  observed  by  Combe.  One  of  the  sailors  died  in 
five  and  a  half  hours  after  eating  the  mussels. 

In  some  recent  cases  reported  by  Schmidtmann,  as 
quoted  by  Briegee,  the  symptoms  were  as  follows  :  Some 
dock  hands  and  their  families  ate  of  cooked  blue  mussels 
which  had  been  taken  near  a  newly  built  dock.  The 
symptoms  appeared,  according  to  the  amount  eaten,  from 
soon  after  eating  to  several  hours  later.  There  was  a  sen- 
sation of  constriction  in  the  throat,  mouth,  and  lips ;  the 
teeth  were  set  on  edge  as  though  sour  apples  had  been 
eaten.  There  was  dizziness,  no  headache ;  a  sensation  of 
flying,  and  an  intoxication  similar  to  that  produced  by 
alcohol.  The  pulse  was  hard,  rapid  (eighty  to  ninety),  no 
elevation  of  temperature,  the  pupils  dilated  and  reaction- 
less.  Speech  was  difficult,  broken  and  jerky.  The  limbs 
felt  heavy ;  the  hands  grasped  spasmodically  at  objects  and 
missed  their  aim.  The  legs  were  no  longer  able  to  support 
the  body,  and  the  knees  knocked  together.  There  was 
nausea,  vomiting,  no  abdominal  pain,  no  diarrhoea.     The 


POISONOUS    MUSSELS.  37 

hauds  became  numb  and  the  feet  cold.  The  sensation  of 
cold  soon  extended  over  the  entire  body,  and  in  some  the 
perspiration  flowed  freely.  There  was  a  feeling  of  suifoca- 
tion,  then  a  restful  and  dreamless  sleep.  One  person  died 
in  one  and  three-quarters  of  an  hour,  another  in  tliree  and 
one-half  hours,  and  a  third  in  fiv^e  hours,  after  eating  of 
the  mussels. 

In  one  of  these  fatal  cases  rigor  mortis  was  marked  and 
remained  for  twenty-four  hours.  The  vessels  of  all  the 
organs  were  distended,  only  the  heart  was  empty.  ViR- 
CHOW  concluded  from  the  conditions  observed  that  the 
blood  had  absorbed  oxvgen  with  great  aviditv.  There  was 
marked  hyperemia  and  swelling  of  the  mucous  membrane 
of  the  stomach  and  intestines,  which  Virchow  pronounced 
an  enteritis.  The  spleen  was  enormously  enlarged  and  the 
liver  showed  numerous  hemorrhafjic  infarctions. 

Many  theories  have  been  advanced  to  account  for  poison- 
ous mussels.  It  was  formerly  believed  that  the  effects  were 
due  to  copper  which  the  animals  obtained  from  the  bottoms 
of  vessels ;  but,  as  Christisox  remarks,  copper  does  not 
produce  these  symptoms.  Moreover,  Christison  made 
analysis  of  the  mussels  which  produced  the  symptoms  ob- 
served by  Combe,  and  was  unable  to  detect  any  copper. 
BoucHARDAT  fouud  copper  in  some  poisonous  mussels,  but 
he  does  not  state  the  amount  of  the  copper  nor  the  source 
of  the  animals. 

Edwards  advanced  the  theory  that  the  symptoms  were 
wholly  due  to  idiosyncrasy  in  the  consumer.  This  may  be 
true  in  some  in.stances  where  only  one  or  two  of  those  par- 
taking of  the  food  are  aflFected,  but  it  certainly  is  not  a 
tenable  hypothesis  in  such  instances  as  those  reported  by 
Combe  and  Schmidtmann,  where  a  large  number  or  all 
those  who  partook  of  the  food  were  affected. 

4 


38  PTOMAINES. 

OoiiDSTEEAM  found  the  livers  of  the  Leith  mussels,  as 
he  thought,  larger,  darker,  and  more  brittle  than  normal, 
and  to  this  diseased  condition  he  attributed  the  ill  effects. 

Lamoroux,  Mohring,  de  Beume,  Chenu,  and  du 
RojSIDEAU  have  supposed  that  the  poisonous  effects  were 
due  to  a  particular  species  of  medusae  upon  which  the  mus- 
sels feed.  De  Beume  found  in  the  vomited  matter  of  one 
23erson,  suffering  from  mussel  poisoning,  some  medusae,  and 
he  states  that  these  are  most  abundant  during  the  summer, 
when  mussels  are  most  frequently  found  to  be  poisonous. 

The  theory  of  Burrow  that  the  animal  is  always  poison- 
ous during  the  period  of  reproduction  has  been  received 
with  considerable  credit.  However,  cases  of  poisoning  have 
occurred  at  different  seasons  of  the  year. 

Crumpe,  in  1872,  suggested  that  there  is  a  species  of 
mussel  which  is  in  and  of  itself  poisonous,  and  this  species 
is  often  mixed  Math  the  edible  variety.  Schmidtmann  and 
ViRCHOW  support  this  idea.  They  state  that  the  poisonous 
species  has  a  brighter  shell,  a  sweeter,  more  penetrating, 
bouillon-like  odor  than  the  edible  kind,  also  that  the  flesh 
of  the  former  is  yellow  and  that  the  water  in  which  they 
are  cooked  is  bluish.  Lohmeyer  also  champions  this 
opinion.  This  theory,  however,  is  opposed  by  the  majority 
of  zo5logists.  MoBius  states  that  the  peculiarities  of  the 
supposed  poisonous  variety  pointed  out  by  ViRCHOW  and 
Schmidtmann  are  really  due  to  the  conditions  under  which 
the  animal  lives,  the  amount  of  salt  in  the  water,  the  tem- 
perature of  the  water,  whether  it  is  moving  or  still  water, 
the  nature  of  the  bottom,  etc.  Finally,  Mobius  states  that 
the  sexual  glands,  which  form  the  greater  part  of  the 
mantle,  are  white  in  the  male  and  yellow  in  the  female. 
However,  it  has  been  shown  later  by  Schmidtmann  and 


POISONOUS    MUSSELS.  39 

ViRCHOWthat  edible  mussels  may  become  poisonous  if  left 
in  filthy  water  for  fourteen  days  or  longer,  and,  on  the 
other  hand,  poisonous  ones  may  become  fit  for  food  if  kept 
for  four  weeks  in  good  water. 

Cats  and  dogs  Mliicli  have  eaten  voluntarily  of  poisonous 
mussels  have  sutl^ered  from  symptoms  similar  to  those  ob- 
served in  man;  and  rabbits  have  been  poisoned  by  the 
administration  of  the  water  in  which  the  food  has  been 
cooked.  A  rabbit  which  was  treated  in  this  manner  by 
ScHMiDTMANX  died  withiu  one  minute.  From  these 
mussels  Brieger  extracted  the  ptomaine  mytilotoxine, 
which  will  be  discussed  in  a  subsequent  chapter.  This 
poison  has  a  curare-like  action.  AVhether  or  not  those 
mussels  which  jirodnce  other  symptoms  also  contain  pto- 
maines, remains  for  future  investigations  to  determine. 

In  1887  three  other  cases  of  mussel  poisoning,  one  fatal 
case,  occurred  at  Wilhelmshaveu,  the  place  which  supplied 
Brieger  with  the  mussels  from  which  he  obtained 
mytilotoxine.  Schmidtmann  has  found  that  non-poison- 
ous mussels  placed  in  the  waters  of  this  bay  soon  become 
poisonous,  and  that  the  poisonous  mussels  from  the  bay 
placed  in  the  open  sea  soon  lose  their  poisonous  properties. 
LiNDER  has  found  in  the  water  of  the  bay  and  in  the  mus- 
sels living  in  it  a  great  variety  of  protozoa,  amoeba,  bacteria, 
and  other  lower  organisms,  which  are  not  found  in  the 
water  of  the  open  sea  nor  in  the  non-poisonous  mussel.  He 
has  also  found  that,  if  the  water  of  the  bay  be  filtered,  non- 
poisonous  mussels  in  it  do  not  become  poisonous.  He 
therefore  concludes  that  poisonous  mussels  are  those  which 
are  suffering  from  disease  due  to  residence  in  filthy  water. 

Brieger  has  tested  dead  and  decomposed  mussels  taken 
from  the  open  sea  for  mytilotoxine,  with  negative  results. 


40  PTOMAINES. 

Poisonous  Oysters  and  Eels. — Pasquier  reported 
cases  of  poisoning  at  Havre  from  the  eating  of  oysters  taken 
from  an  artificial  bed  which  had  been  established  near  the 
outlet  of  a  drain  from  a  public  water-closet.  Christison 
says  that  an  "  unusual  prevalence  of  colic,  diarrhoea,  and 
cholera"  at  Dunkirk  was  believed  to  have  been  traced  to  an 
importation  of  unwholesome  oysters  from  the  Normandy 
coast.  Vaughan  and  Novy  obtained  tests  for  tyrotoxicon 
in  the  liquor  of  some  decomposed  oysters  which  had  caused 
illness  in  many  people  at  a  church  festival. 

ViREY  states  that  many  persons  were  attacked  with 
violent  pain  and  diarrhoea  a  few  hours  after  eating  a  pate 
made  of  eels  from  a  stagnant  cattle-ditch  near  Orleans, 
also  that  similar  cases  have  occurred  in  various  parts  of 
France,  and  that  domestic  animals  have  been  killed  by 
eating  the  remains  of  the  poisonous  dish. 

Sausage  Poisoning. — This  is  also  known  as  botulis- 
mus  and  allantiasis.  While  considerable  diversity  has 
been  observed  in  symptoms  of  sausage  poisoning,  we 
cannot  divide  the  cases  into  classes  from  their  symp- 
tomatology as  has  been  done  in  mussel  poisoning.  The 
first  effects  may  manifest  themselves  at  any  time  from 
one  hour  to  twenty-four  hours  after  eating  of  the  sausage, 
and  cases  are  recorded  in  which,  it  is  stated,  no  symptoms 
appeared  until  several  days  had  passed.  However,  we 
must  remember  that  trichinosis  was  frequently,  in  former 
times,  classed  as  sausage  poisoning,  and  it  is  highly  prob- 
able that  these  cases  of  long  delay  in  the  appearance  of  the 
symptoms  were  really  not  due  to  putrefaction,  but  to  the 
presence  of  parasites  in  the  meat.  A  large  majority  of  the 
one  hundred  and  twenty-four  cases  more  recently  reported 
by  MiJLLER  sickened  within  twenty-four  hours,  and  out  of 


SAUSAGE    POISONING.  41 

the  forty-eight  of  these  which  were  fatal,  six  died  within 
the  first  twenty-four  hours.  At  first  there  is  dryness  of 
the  mouth,  constriction  of  the  throat,  uneasiness  in  the 
stomach,  nausea,  vomiting,  vertigo,  indistinctness  of  vision, 
dilatation  of  the  pupils,  difficulty  iu  swallowing,  and  usu- 
ally diarrhoea,  though  obstinate  constipation  may  exist 
from  the  first.  There  is,  as  a  rule,  a  sensation  of  suffoca- 
tion, and  the  breathing  becomes  labored.  The  pulse  is 
small,  thready,  and  rapid.  In  some  cases  the  radial  pulse 
may  be  imperceptible.  Marked  nervous  prostration  and 
muscular  debility  follow.  These  symptoms  vary  greatly 
in  prominence  in  individual  cases.  The  retching  and 
vomiting,  which  may  be  most  distressing  and  persistent  in 
some  instances,  in  others  are  trivial  at  the  beginning  and 
soon  cease  altogether.  The  same  is  true  of  the  diarrhoea. 
As  a  rule,  the  functions  of  the  brain  proceed  normally,  but 
there  may  be  delirium,  then  coma  and  death.  In  some 
there  are  marked  convulsive  movements,  especially  of  the 
limbs,  in  others,  paralysis  may  l^e  an  early  and  marked 
symptom.  The  pupils  may  dilate,  then  become  normal 
and  again  dilate.  There  is  frequently  ptosis,  and  paralysis 
of  the  muscles  of  accommodation  is  not  rare.  Complete 
blindness  has  followed  in  a  few  instances. 

The  fatality  varies  greatly  in  different  outbreaks.  In 
1820  Keener  collected  reports  of  seventy-six  cases,  of 
which  thirty-seven  were  fatal.  In  his  next  publication 
(1822)  he  increased  the  number  to  one  hundred  and  fifty- 
five  ca.ses,  with  eighty-four  fatal  results.  This  gave  a  mor- 
tality of  over  fifty  per  cent.,  while  in  one  outbreak  re- 
ported by  ]\IuLLER  the  mortality  was  less  than  two  per 
cent. 

A  large  proportion  of  the  cases  of  sau.sage  poisoning 
have  occurred  in  Wiirtemberg  and  the  immediately  adja- 

4* 


42  PTOMAINES. 

cent  portions  of  Baden.  This  fact  has,  without  doubt,  been 
correctly  ascribed  to  the  methods  there  practised  of  prepar- 
ing and  curing  the  sausage.  It  is  said  to  be  common  for 
the  people  to  use  the  blood  of  the  sheep,  ox,  and  goat  in 
the  preparation  of  this  article  of  diet.  Moreover,  the  blood 
is  kept  sometimes  for  days  in  wooden  boxes  and  at  a  high 
temperature  before  it  is  used.  In  these  cases  it  is  altogether 
likely  that  putrefaction  progresses  to  the  poisonous  stage 
before  the  process  of  curing  is  begun.  However,  cases  of 
poisoning  have  occurred  from  beef  and  pork  sausages  as 
well. 

Moreover,  the  method  of  curing  employed  in  Wiirtem- 
berg  favors  putrefaction.  A  kind  of  sausage  known  as 
"  blunzen  "  is  made  by  filling  the  stomachs  of  hogs  with 
the  meat.  In  curing,  the  interior  of  this  great  mass  is  not 
acted  upon,  and  putrefaction  sets  in.  The  curing  is  usu- 
ally done  by  hanging  the  sausage  in  the  chimney.  At 
night  the  fire  often  goes  out  and  the  meat  freezes.  The 
alternate  freezing  and  thawing  render  decomposition  more 
easy.  The  interior  of  the  sausage  is  generally  the  most 
poisonous.  Indeed,  in  many  instances  those  who  have 
eaten  of  the  outer  portion  have  been  unharmed ;  while 
those  who  have  eaten  of  the  interior  of  the  same  sausage 
have  been  most  seriously  affected. 

Many  German  writers  state  that  when  a  poisonous  saus- 
age is  cut,  the  putrid  portion  has  a  dirty,  grayish-green 
color,  and  a  soft,  smeary  consistency.  A  disagreeable  odor, 
resembling  that  of  putrid  cheese,  is  perceptible.  The  taste 
is  unpleasant,  and  sometimes  a  smarting  of  the  mouth  and 
throat  is  produced.  Post-mortem  examination  after  saus- 
age poisoning  shows  no  characteristic  lesion.  It  is  gener- 
ally stated  that  putrefaction  sets  in  very  tardily,  but 
MtJLLER  shows  that  no  reliance  can  be  placed  upon  this 


SAUSAGE    POISONING.  43 

point,  and  states  that  out  of  forty-eight  recorded  autopsies, 
it  was  especially  stated  in  eleven  that  putrefaction  rapidly 
tleveloped.  In  some  instances  there  has  been  noticed 
hyperjeniia  of  the  stomach  and  intestinal  canal,  but  this  is 
by  no  means  constant.  The  liver  and  brain  have  been 
reported  as  congested,  but  this  would  result  from  the 
failure  of  the  heart,  and  would,  by  no  means,  be  charac- 
teristic of  poisoning  with  sausage. 

Von  Faber,  in  1821,  observed  sixteen  persons  who 
were  made  sick  by  eating  fresh,  unsmoked  sausage  made 
from  the  flesh  of  a  pig  which  had  suffered  from  an  abscess 
on  the  neck.  Five  of  the  patients  died.  The  symptoms 
were  as  follows :  There  was  a  constriction  of  the  throat, 
difficulty  in  swallowing,  retching,  vomiting,  colic- like 
pains,  vertigo,  hoarseness,  dimness  of  vision,  and  headache. 
Later  and  in  severer  cases,  there  was  complete  exhaustion, 
and,  finally,  paralysis.  The  eyeballs  were  retracted,  the 
pupils  were  sometimes  dilated,  then  contracted  ;  they  did 
not  respond  to  light;  there  was  paralysis  of  the  upper  lids. 
The  tonsils  were  swollen,  but  not  as  in  tonsillitis.  Liquids 
which  were  not  irritating  could  be  carried  as  far  as  the 
oesophagus,  when  they  were  then  ejected  from  the  mouth 
and  nose  with  coughing.  Solid  foods  could  not  be  swal- 
lowed at  all.  On  the  back  of  the  tongue  and  in  the 
pharynx  there  was  observed  a  puriform  exudate. 

Obstinate  constipation  existed  in  all,  while  the  sphincter 
ani  was  paralyzed.  The  breathing  was  easy,  but  all  had  a 
croupous  cough.  The  skin  was  dry.  There  was  incon- 
tinence of  urine.  There  was  no  delirium  and  the  mind 
remained  clear  to  the  last. 

Post-mortem  examinations  were  held  on  four.  The  skin 
was  rough — "goose-skin."  The  abdomen  was  retracted. 
The  large  vessels  in  the  upper  part  of  the  stomach  were 


44  PTOMAINES. 

filled  with  black  blood.  The  contents  of  the  stomach  con- 
sisted of  a  reddish-brown,  semi-fluid  substance,  which  gave 
off  a  repugnant,  acid  odor.  In  one  case  the  omentum  was 
found  greatly  congested.  The  large  intestine  was  very- 
pale,  and  the  right  ventricle  of  the  heart  was  filled  with 
dark  fluid  blood. 

ScHUZ  cites  thirteen  cases  of  poisoning  from  liver  saus- 
age in  which  the  symptoms  differed  from  the  foregoing  in 
the  following  respects : 

(1)  In  only  one  out  of  the  thirteen  was  there  constipa- 
tion ;  all  the  others  had  numerous  watery,  typhoid-like 
stools. 

(2)  Symptoms  involving  the  sense  of  sight  were  present 
in  only  three ;  in  all  the  pupils  were  unchanged. 

(3_)  The  croupous  cough  was  wholly  wanting;  though 
in  many  there  was  complete  loss  of  voice.  Difficulty  of 
swallowing  was  complained  of  by  only  one. 

(4)  Delirium  was  marked  in  all;  and  in  one  the  dis- 
turbance of  the  mental  faculties  was  prominent  for  several 
weeks. 

(5)  There  were  no  deaths. 

(6)  The  time  between  eating  the  sausage  and  the  appear- 
ance of  the  symptoms  varied  from  eighteen  to  twenty-four 
hours,  and  the  duration  of  sickness  from  one  to  four  weeks; 
though  in  one  case  complete  recovery  did  not  occur  until 
after  two  and  one-half  months. 

The  sausages  were  not  smoked,  and  all  observed  a  garlic 
odor,  though  no  garlic  had  been  added  to  the  meat. 

Teipe  reports  sixty-four  cases.  The  symptoms  came  on 
from  three  and  one-half  to  thirty-six  hours  after  eating. 
The  stools  were  frequent,  watery,  and  of  offensive  odor. 
In  some  there  was  delirium.  One  died.  In  the  fatal  case 
the  hands  and  face  were  cold  and  sM-ollen.    The  pulse  was 


SAUSAGE    POISONING.  45 

rapid  and  weak.  The  pupils  were  contracted,  but  responded 
to  light.     The  small  intestine  was  found  inflamed. 

Hedinger  reports  tlie  case  of  a  man  and  a  woman  with 
the  usual  symptoms,  but  durino-  recovery  the  dilatation  of 
the  pupils  was  followed  by  contraction.  Birds  ate  of  this 
sausage,  and  were  not  affected. 

RoSER  reports  cases  in  which  there  were  found,  after 
death,  abscesses  of  the  tonsils,  a  dark,  bluish  appearance 
of  the  mucous  membrane  of  the  pharynx,  larynx,  and 
bronchial  tubes,  dark  redness  of  the  fundus  of  the  stomach, 
and  circumscribed,  gray,  red,  and  black  spots  on  the  mucous 
membrane  of  the  intestine.  The  liver  was  brittle,  and  the 
spleen  enlarged. 

Many  theories  concerning  the  nature  of  the  active  prin- 
ciple of  poisonous  sausage  have  been  advanced.  It  was 
once  believed  to  consist  of  pyroligneous  acid,  which  was 
supposed  to  be  absorbed  by  the  meat  from  the  smoke  used 
in  curing  it ;  but  it  was  soon  found  that  unsmoked  sausage 
might  be  poisonous  also.  Emmert  believed  that  the  active 
agent  was  hydrocyanic  acid,  and  Jager's  theory  supposed 
the  presence  of  picric  acid.  But  these  acids  are  not  found 
in  poisonous  sausage,  and,  moreover,  their  toxicological 
effects  are  wholly  unlike  those  observed  in  sausage  poison- 
ing. As  we  have  elsewhere  seen,  Kerxer  believed  that 
he  had  found  the  poisonous  principle  in  a  fatty  acid.  This 
theory  was  supported  by  Dann,  BucHNER,and  Schumann. 
Kerner  believed  the  poison  to  consist  of  either  caseic  or 
sebacic  acid,  or  both,  while  Buchner  named  it  acidum 
botulinicum  ;  but  the  acids  of  the  former  proved  to  be  inert, 
and  that  of  the  latter  to  have  no  existence.  Schloss- 
berger  first  suggested  that  the  poisonous  substance  is  most 
probably  basic  in  character,  and  he  found  an  odoriferous, 
amraouiacal  base  which  could  not  be  found  in  good  sausage, 


46  PTOMAINES. 

and  which  did  not  correspond  to  any  known  amides,  imides, 
or  nitril  bases.  However,  this  substance  has  not  been 
obtained  by  any  one  else,  nor  has  it  been  demonstrated  to 
be  poisonous. 

LiEBiG,  DuFLAS,  HiRSCH,  and  Simon  believed  in  the 
presence  of  a  poisonous  ferment.  Van  den  Corput. 
described  sarcina  botulina,  which  was  believed  to  constitute 
the  active  agent.  Muller,  Hoppe-Seyler,  and  others 
have  found  various  microdrganisms,  and  Virchow,  Eich- 
ENBERG,  and  others  have  examined  microscopically  the 
blood  of  persons  poisoned  with  sausage.  Recently,  Ehren- 
BERG  has  attempted  to  isolate  the  poisonous  substance  by 
employing  Brieger's  method,  but  he  obtained  only  inert 
substances. 

In  the  light  of  the  knowledge  of  to-day  concerning  the 
nature  of  putrefaction,  there  can  scarcely  be  a  doubt  that 
the  active  agent  of  poisonous  sausage  consists  of  an  easily 
decomposable  base,  and  we  predict  its  isolation  in  the  very 
near  future. 

Poisonous  Ham. — Under  this  head,  we  shall  not  discuss 
cases  of  poisoning  from  trichina  or  other  parasites,  but  shall 
refer  only  to  those  instances  in  which  the  toxic  agent  has 
originated  in  putrefactive  changes.  A  number  of  such 
cases  have  been  observed  within  the  past  ten  years,  but  only 
a  few  of  them  have  been  investigated  scientifically.  The  best 
known  of  these,  as  well  as  the  most  thoroughly  studied,  is 
the  Wellbeck  poisoning,  which  Ballard  investigated  suc- 
cessfully. In  June,  1880,  a  large  number  of  persons 
attended  a  sale  of  timber  and  machinery  on  the  estate  of  the 
Duke  of  Portland,  at  Wellbeck.  The  sale  continued  four 
days,  and  lunches  were  served  by  the  proprietress  of  a 
neighboring  hotel.     The  refreshments   consisted   of  cold, 


POISONOUS    HAM.  47 

boiled  ham,  cold,  boiled,  or  roasted  beef,  cold  beefsteak  pie, 
mustard  and  salt,  br^ad  and  cheese,  pickles,  and  Chutney 
sauce.  The  drinks  were  bottle  anil  draught  beer,  spirits, 
ginjjer  beer,  lemonade,  and  water.  Many  were  poisoned, 
and  Bai.lard  obtained  tiic  particulars  of  seventy-two  cases, 
among  which  there  were  four  deaths.  The  symptoms  are 
given  by  Ballard  as  follows : 

"  I  propose  to  speak  of  the  attacks  under  the  name  of 
'diarrhoeal  illness,' because  diarrhoea  was  the  most  constant 
of  all  the  symptoms  observed,  and  the  other  symptoms 
were  in  some  respects  so  peculiar  that  I  am  indisposed  to 
give  to  the  disease  any  name  otherwise  generally  recognized. 
As  might  have  been  anticipated  from  our  experience  of 
diseases  in  general,  there  were  varieties  in  severity  among 
the  cases  investigated  ;  and  symptoms  strongly  marked  in 
some,  were  slightlv  marked  or  altogether  wanting  in  others. 
Perhaps  I  shall  do  the  best  service  by  giving  first  a  general 
sketch  of  the  course  of  the  illness,  subsequently  illustrating 
it  by  a  description  of  a  few  well-marked  cases. 

"A  period  of  incubation  preceded  the  illness.  In  fifty- 
one  cases  where  this  could  be  accurately  determined,  it  was 
twelve  hours  or  less  in  five  cases ;  between  twelve  and 
thirty-six  hours  in  thirty-four  cases;  between  thirty-six 
and  forty-eight  hours  in  eight  cases ;  and  later  than  this  in 
only  four  cases.  In  many  cases  the  first  definite  symptoms 
occurred  suddenly,  and  evidently  unexpectedly,  but  in  some 
cases  there  were  observed  during  the  incubation  more  or 
less  feeling  of  languor  and  ill  health,  loss  of  appetite, 
nausea,  or  fugitive,  griping  pains  in  the  belly.  In  about 
a  third  of  the  cases,  the  first  definite  symptom  was  a  sense 
of  chilliness  usually  with  rigors,  of  trembling,  in  one  case 
accompanied  by  dyspnoea ;  in  a  few  cases  it  was  giddiness 
with  faintness,  sometimes  accompanied  by  a  cold  sweat  and 


48  PTOMAINES. 

tottering ;  in  others,  the  first  symptom  was  headache  or 
pain  somewhere  in  the  trunk  of  the  body — e.g.,  in  the 
chest,  back,  between  the  shoulders,  or  in  the  abdomen,  to 
which  part  the  pain,  wherever  it  might  have  commenced, 
subsequently  extended.  In  one  case  the  first  symptom 
noticed  was  a  difficulty  in  swallowing.  In  two  cases  it  was 
intense  thirst.  But  however  the  attack  may  have  com- 
menced, it  was  usually  not  long  befi^re  pain  in  the  abdomen, 
diarrhoea,  and  vomiting  came  on,  diarrhoea  being  of  more 
certain  occurrence  than  vomiting.  The  pain  in  several 
cases  commenced  in  the  chest  or  between  the  shoulders,  and 
extended  first  to  the  upper  and  then  to  the  lower  part  of 
the  abdomen.  It  was  usually  very  severe  indeed,  quickly 
producing  prostration  or  faintness,  with  cold  sweats.  It 
was  variously  described  as  crampy,  burning,  tearing,  etc. 
The  diarrhoeal  discharges  were  in  some  cases  quite  unre- 
strainable,  and  (where  a  description  of  them  could  be  ob- 
tained) were  said  to  have  been  exceedingly  offensive  and 
usually  of  a  dark  color.  Muscular  weakness  was  an  early 
and  very  remarkable  symptom  in  nearly  all  the  cases,  and 
in  many  it  was  so  great  that  the  patient  could  only  stand 
by  holding  on  to  something.  Headache,  sometimes  severe, 
was  a  common  and  early  symptom ;  and  in  most  cases  there 
was  thirst  often  intense  and  most  distressing.  The  tongue, 
when  observed,  was  described  usually  as  thickly  coated 
with  a  brown,  velvety  fur,  but  red  at  the  tip  and  edges. 
In  the  early  stage  the  skin  was  often  cold  to  the  touch,  but 
afterward  fever  set  in,  the  temperature  rising  in  some 
cases  to  101°,  103°,  and  104°.  In  a  few  severe  cases 
where  the  skin  was  actually  cold,  the  patient  complained  of 
heat,  insisted  on  throwing  off  the  bedclothes,  and  was  very 
restless.  The  pulse  in  the  height  of  the  illness  became 
quick,  counting  in   some  cases   100  to  128.     The  above 


POISONOUS    HAM.  49 

were  the  symptoms  most  frequently  noted.  Other  symp- 
toms occurred,  however,  some  in  a  few  cases,  and  some  only 
in  solitary  cases.  These  I  now  proceed  to  enumerate. 
Excessive  sweating,  cramps  in  the  legs,  or  in  both  legs  and 
arms,  convulsive  flexion  of  the  hands  or  fingers,  muscular 
tsvitciiings  of  the  face,  shoulders,  or  hands,  aching  pain  in 
the  shoulders,  joints,  or  extremities,  a  sense  of  stiffness  of 
the  joints,  prickling  or  tingling  or  numbness  of  the  hands 
lasting  far  into  convalescence  in  some  cases,  a  sense  of 
general  compression  of  the  skin,  drowsiness,  hallucinations, 
imperfection  of  vision,  and  intolerance  of  light.  In  three 
cases  (one,  that  of  a  medical  man)  there  was  observed  yel- 
lowness of  the  skin,  either  general  or  confined  to  the  face 
and  eyes.  In  one  case,  at  a  late  stage  of  the  illness,  there 
was  some  pulmonary  congestion,  and  an  attack  of  what  was 
regarded  as  gout.  In  the  fatal  cases,  death  was  preceded 
by  collapse  like  that  of  cholera,  coldness  of  the  surface, 
pinched  features  and  blueuess  of  the  fingers  and  toes,  and 
around  the  sunken  eyes.  The  debility  of  convalescence 
was  in  nearly  all  cases  protracted  to  several  weeks. 

"The  mildest  cases  were  characterized  usually  Ijy  little 
remarkable  beyond  the  following  symptoms,  viz.,  abdominal 
pain.s,  vomiting,  diarrhoea,  thirst,  headache,  and  muscular 
weakness;  any  one  or  two  of  which  might  be  absent." 

The  cause  of  this  illness  was  traced  conclusively  to  the 
hams  eaten.  Klein  found  in  the  meat  a  bacillus,  cultures 
of  which  were  used  for  inoculating  animals.  These  inocu- 
lations were  found  generally  to  be  followed  by  pneumonia. 
No  attempt  was  made  to  isolate  a  ptomaine. 

Later,  Ballard  reported  fifteen  cases  with  symptoms 
similar  to  the  above,  and  with  one  death,  from  eating  baked 
pork.  Not  all  of  those  who  ate  of  this  pork  were  made 
sick.     This  might  have  been  due  to  inequality  in  the  putre- 

5 


50  PTOMAINES. 

factive  changes  in  diiFerent  portions  of  the  meat,  or  it  may 
have  been  due  to  differences  in  temperature  in  various  por- 
tions of  the  meat  during  the  cooking.  In  the  blood,  peri- 
cardial fluid,  and  lungs  of  the  fatal  case,  Klein  observed 
bacilli  similar  to  those  discovered  in  the  Wellbeck  inquiry. 
Pneumonia  was  produced  by  inoculating  guinea-pigs  and 
mice  with  these  bacilli. 

August  29,  1887,  256  soldiers  and  36  citizens  at  Middle- 
burg,  Holland,  were  taken  sick  after  eating  meat  from  a 
cow  which  had  been  killed  while  suffering  from  puerperal 
fever.  The  symptoms  were  nausea,  vomiting,  purging, 
elevation  of  temperature,  and  prostration.  In  some  there 
were  observed  dizziness,  sleepiness,  and  dilatation  of  the 
pupil.  After  a  few  days  these  symptoms  gradually  disap- 
peared, and  in  many  an  eczematous  eruption  of  the  lips 
gave  annoyance.  Pigs,  cats,  and  dogs,  which  ate  of  the 
oflFal  of  this  animal,  w^ere  also  made  sick.  Thorough 
cooking  did  not  destroy  the  poison,  and  those  who  took 
soup  and  bouillon  made  from  the  meat  were  affected  like 
those  who  ate  of  the  muscular  fibre.  In  most  of  the  cases 
the  symptoms  came  on  within  twelve  hours  after  eating  the 
meat. 

Ou  a  fete-day  at  Zurich,  in  1839,  600  persons  who  were 
fed  upon  cold  veal  and  ham  Avere  taken  ill,  with  shivering, 
giddiness,  vomiting,  and  diarrhoea.  Some  were  delirious 
and  others  were  salivated,  the  saliva  being  extremely  fetid. 
In  the  worst  cases,  there  were  involuntary  stools,  collapse, 
and  death.  The  cause  was  traced  to  putrefactive  changes 
in  the  meat. 

SiEDLEE  reports  an  instance  of  four  persons  having  been 
made  sick  by  eating  decomposed  goose-grease.  There  were 
giddiness,  prostration,  and  violent  vomiting.  No  metallic 
poison  could  be  found.     The  grease  was  rancid,  of  repul- 


POISONOUS    CANNED    MEATS.  61 

sive  odor,  and  three  ounces  of  it  given  to  a  dog  produced 
the  same  symptoms  whicli  had  been  observed  in  the 
persons. 

Christison  reports  a  number  of  cases  in  which  persons 
were  seriously,  a  few  fatally,  affected  by  eating  various 
kinds  of  meat  which  had  undergone  partial  putrefaction. 

Ollivier  found  six  persons  poisoned,  four  of  them 
fatally,  by  eating  of  decomposed  mutton.  He  also  men- 
tions the  poisoning  of  a  family  of  three  with  ham  pie. 
Chemical  analysis  failed  to  reveal  the  presence  of  any 
poison. 

BoUTiONY,  having  failed  to  find  any  poison  in  the  meat 
furnished  at  a  festival,  and  to  which  the  serious  illness  of 
many  was  attributed,  made  a  meal  of  stuifed  turkey  fur- 
nished by  the  same  dealer,  but  after  a  short  time  his  coun- 
tenance became  livid,  his  pulse  small  and  feeble,  a  cold 
sweat  bathed  his  body,  and  violent  vomiting  and  purging 
followed.     His  recovery  was  slow. 

Geiseler  observed  nausea,  vomiting,  purging,  and 
delirium  after  eating  of  bacon  which  was  imperfectly  cured. 

Poisonous  Canned  Meats. — Cases  of  poisoning  from ' 
eating  canned  meats  have  become  quite  frecpient.  Although 
it  may  be  possible  that  in  some  instances  the  untoward 
effects  result  from  metallic  poisoning,  in  the  great  majority 
of  cases  the  poisonous  principles  are  formed  by  putrefactive 
changes.  In  many  instances  it  is  probable  that  decomposi- 
tion begins  after  the  can  is  opened  by  the  consumer.  In 
others,  the  canning  is  carelessly  done  and  putrefaction  is 
far  advanced  before  the  food  reaches  the  consumer.  In 
still  other  instances,  the  meat  may  be  taken  from  diseased 
animals,   or  it  may    undergo  putrefactive  changes   before 


52  .  PTOMAINES. 

the  canning.     What  is  true  of  canned  meats  is  also  true  of 
canned  fruits  and  vegetables. 

Dr.  AsHWORTH,  of  >Smithland,  Iowa,  has  reported  to  us 
three  fatal  cases  of  poisoning  from  canned  apricots.  An 
infant,  ^Yhich  was  only  eight  days  old,  and  which  must 
have  received  the  poison  from  its  mother's  breast,  died 
within  a  few  hours.  The  mother  died  forty-three  hours 
after  eating  the  apricots,  and  the  father  on  the  sixth  day. 
The  symptoms  corresponded  with  those  of  poisoning  by 
tyrotoxicon.  However,  it  seems  that  no  analysis  was 
made,  and  these  may  have  been  cases  of  mineral  poisoning. 

PoLSONOUS  Cheese. — In  1827  Huxnefeld  made  some 
analyses  of  poisonous  cheese,  and  experimented  with  ex- 
tracts upon  the  lower  animals  He  accepted  the  ideas  of 
Kerxee  in  regard  to  poisonous  sausage  in  a  somewhat 
modified  form,  and  thought  the  active  agents  to  be  sebacic 
and  caseic  acids.  About  the  same  time,  Seeturner, 
making  analyses  of  poisonous  cheese  for  Westrumb,  also 
traced  the  poisonous  principles,  as  he  supposed,  to  these 
fatty  acids.  We  see  from  this  that  during  the  first  part  of 
the  present  century  the  fatty  acid  theory,  as  it  may  be 
called,  was  generally  accepted. 

In  1848,  Christison,  after  referring  to  the  work  of 
HuNXEFELD  aud  Serturxer,  made  the  following  state- 
ment :  "  His  (Hiinnefeld's)  experiments,  however,  are  not 
quite  conclusive  of  the  fact  that  these  fatty  acids  are  really 
the  poisonous  principles,  as  he  has  not  extended  his  experi- 
mental researches  to  the  caseic  and  sebacic  acids  prepared 
in  the  ordinary  way.  His  views  will  probably  be  altered 
and  simplified  if  future  experiments  should  confirm  the 
late  inquiries  of  Bracoxnot,  who  has  stated  that  Proust's 


POISONOUS    CHEESE.    .  53 

caseic  acid  is  a  modification  of  acetic  acid  combined  with 
an  acrid  oil." 

In  1852  ScHLOSSBERGER  made  experiments  with  tlie 
pure  fatty  acids  and  demonstrated  their  freedom  from  poi- 
sonous properties.  Tliese  experiments  have  been  verified 
repeatedly,  so  that  now  it  is  well  known  that  all  the  fatty 
acids  obtainable  from  cheese  are  devoid  of  poisonous  pro- 
perties. 

It  may  be  remarked  here,  that  there  is  every  probability 
that  the  poisonous  substance  was  present  in  the  extracts  ob- 
tained by  the  older  chemists.  Indeed,  we  may  say  that 
this  is  a  certainty,  since  the  administration  of  these  extracts 
to  cats  was,  in  some  instances  at  least,  followed  by  fatal  re- 
sults. The  great  mass  of  these  extracts  consisted  of  fatty 
acids,  and  as  the  chemists  could  find  nothing  else  present, 
they  very  naturally  concluded  that  the  fatty  acids  them- 
selves constituted  the  j)oisonous  substance. 

Since  the  overthrow  of  the  fatty  acid  theory,  various  con- 
jectures have  been  made,  but  none  of  them  is  worthy  of 
consideration. 

We  make  the  following  quotations  from  some  of  the  best 
authorities  who  wrote  during  the  first  half  of  the  present 
decade  upon  this  subject : 

HiLLER  says  :  "  Nothing  definite  is  known  of  the  nature 
of  cheese  poison.  Its  solubility  seems  established  from  an 
observation  by  Husemaxn,  a  case  in  which  the  poison  was 
transmitted  from  a  nursing  mother  to  her  child." 

HuSEMAXX  wrote  as  follows  :  "The  older  investigations 
of  the  chemical  nature  of  cheese  poison,  which  led  to  the 
belief  of  putrefactive  cheese  acids  and  other  problematic 
substances,  are  void  of  all  trustworthiness,  and  the  dis- 
covery of  the  active  principle  of  poisonous  cheese  may  not 
be  looked  for  in  the  near  future,  on  account  of  the  proper 

5* 


54  PTOMAINES. 

animals  for  controlling  the  experiments  with  the  extracts, 
as  dogs  can  eat  large  quantities  of  poisonous  cheese  with- 
out its  producing  any  effect." 

Brieger  stated  in  1885  :  "All  kinds  of  conjectures  con- 
cerning the  nature  of  this  poison  have  been  formed,  but  all 
are  even  devoid  of  historical  interest ;  because  they  are  not 
based  upon  experimental  investigations.  My  own  experi- 
ments toward  solving  this  question  have  not  progressed 
v^ery  far." 

In  the  above  quotation  we  think  that  Brieger  has 
hardly  done  justice  to  the  work  of  Hunnefeld  and  Ser- 
turner.  Their  labors  can  hardly  be  said  to  be  wholly 
devoid  of  historical  interest,  and  they  certainly  did  employ 
the  experimental  method  of  inquiry.  We  shall  soon  see  as 
to  the  correctness  of  the  prediction  of  Husemann  as  given 
above. 

In  the  years  1883  and  1884  there  were  reported  to  the 
Michigan  State  Board  of  Health  about  three  hundred  cases 
of  cheese  poisoning.  As  a  rule,  the  first  symptoms  ap- 
peared within  from  two  to  four  hours  after  eating  the 
cheese.  In  a  few  the  symptoms  were  delayed  from  eight 
to  ten  hours  and  were  very  slight.  The  attending  physi- 
cians reported  that  the  gravity  of  the  symptoms  varied  with 
the  amount  of  cheese  eaten,  but  no  one  who  ate  of  the  poi- 
sonous cheese  wholly  escaped.  One  physician  reported  the 
following  symptoms  :  "  Every  one  who  ate  of  the  cheese 
was  taken  with  vomiting,  at  first  of  a  thin,  watery,  later  a 
more  consistent  reddish  colored  substance.  At  the  same 
time  the  patient  suffered  from  diarrhoea  with  watery  stools. 
Some  complained  of  pain  in  the  region  of  the  stomach.  At 
first  the  tongue  was  white,  but  later  it  became  red  and  dry, 
the  pulse  was  feeble  and  irregular ;  countenance  pale,  with 
marked  cyanosis.     One  small  boy,  whose  condition  seemed 


POISONOUS    CHEESE.  55 

very  critical,  was  covered  all  over  the  body  with  bluish 
spots." 

Dryness  and  constriction  of"  the  throat  were  complained 
of  by  all.  In  a  few  cases  the  vomiting  and  diarrhoea  were 
followed  by  marked  nervous  prostration,  and  in  some  dila- 
tation of  the  pupils  was  ol)served. 

Notwithstanding  the  severity  of  the  symptoms  in  many, 
there  was  no  fatal  termination  among  these  cases,  tiiough 
several  deaths  from  cheese  poisoning  in  other  outbreaks 
have  occurred.  Many  of  the  physicians  at  first  diagnosed 
the  cases  from  the  symptoms  as  due  to  arseni(!al  poisoning, 
and  on  this  supposition  some  administered  ferric  hydrate. 
Others  gave  alcohol  and  other  stimulants  and  treated  upon 
the  expectant  plan. 

Vaugiian,  to  whom  the  cheese  was  sent  for  analysis, 
made  the  following  report :  ^'All  of  these  three  hundred 
cases  were  caused  by  eating  of  twelve  different  cheeses.  Of 
these,  nine  were  made  at  one  factory,  and  one  each  at  three 
other  factories.  Of  each  of  the  twelve  I  received  smaller 
or  larger  pieces.  Of  each  of  ten  I  received  only  small 
amounts.  Of  each  of  the  other  two  I  received  about 
eighteen  kilograms.  The  cheese  was  in  good  condition 
and  there  was  nothing  in  the  taste  or  odor  to  excite  sus- 
picion. However,  from  a  freshly  cut  surface  there  exuded 
numerous  drops  of  a  slightly  opalescent  fluid  which  red- 
dened litmus  paper  instantly  and  intensely.  Although,  as 
I  have  stated,  I  could  discern  nothing  peculiar  in  the  odor, 
if  two  samples,  one  of  good,  the  other  of  poisonous  cheese, 
were  placed  before  a  dog  or  cat,  the  animal  would  invari- 
ably select  the  good  cheese.  But  if  only  poisonous  cheese 
was  offered,  and  the  animal  was  hungry,  it  would  partake 
freely.  A  cat  was  kept  seven  days  and  furnished  only 
poisonous  cheese  and  water.     It  ate  freely  of  the  cheese 


56  PTOMAINES. 

and  manifested  no  untoward  symptoms.  After  the  seven 
days  the  animal  was  etherized  and  abdominal  section  was 
made.  ^Nothing  abnormal  could  he  found.  I  predicted, 
however,  in  one  of  my  first  articles  on  poisonous  cheese, 
that  the  isolated  poison  would  aifect  the  lower  animals. 
As  to  the  trutli  of  this  prediction  we  will  see  later. 

"Mv  friend,  Dr.  Steenbeeg,  the  eminent  bacteriologist, 
found  in  the  opalescent  drops  above  referred  to,  numerous 
micrococci.  But  inoculations  of  rabbits  with  these  failed 
to  produce  any  results. 

"At  first  I  made  an  alcoholic  extract  of  the  cheese.  After 
the  alcohol  was  evaporated  in  vacuo  at  a  low  temperature, 
a  residue  consisting  mainly  of  fatty  acids  remained.  I  ate 
a  small  bit  of  this  residue,  and  found  that  it  produced  dry- 
ness of  the  throat,  nausea,  vomiting,  and  diarrhoea.  The 
mass  of  this  extract  consisted  of  fats  and  fatty  acids,  and 
for  some  weeks  I  endeavored  to  extract  the  poison  from 
these  fats,  but  all  attempts  were  unsuccessful.  I  then  made 
an  aqueous  extract  of  the  cheese,  filtered  this  and  drinking 
some  of  it,  found  that  it  also  was  poisonous.  But  after 
evaporating  the  aqueoas  extract  to  dryness  on  the  water- 
bath  at  100°,  the  residue  thus  obtained  was  not  poisonous. 
From  this  I  ascertained  that  the  poison  was  decomposed  or 
volatilized  at  or  below  the  boiling  point  of  water.  I  then 
tried  distillation  at  a  low  temperature,  but  by  this  the 
poison  seemed  to  be  decomposed. 

"Finally,  I  made  the  clear,  filtered  aqueous  extract, 
which  was  highly  acid,  alkaline  with  sodium  hydrate,  agi- 
tated this  with  ether,  removed  the  ether,  and  allowed  it  to 
evaporate  spontaneously.  The  residue  was  highly  poison- 
ous. By  resolution  in  water  and  extraction  with  ether,  the 
poison  was  separated  from  foreign  substances.  As  the  ether 
took  up  some  water,  this  residue  consisted  of  an  aqueous 


POISONOUS    CHEESE.  57 

solution  of  the  poison.  After  this  was  allowed  to  stand  for 
some  hours  in  vacuo  over  sulphuric  acid,  the  poison  sepa- 
rated in  needle-shaped  crystals.  From  some  samples  the 
poison  crystallized  from  the  first  evaporation  of  the  etlier, 
and  without  standiuii-  in  vacuo.  This  happened  only  when 
the  cheese  contained  a  comparatively  large  amount  of  the 
poison.  Ordinarily,  the  microscope  was  nece&sary  to  detect 
the  crystalline  shape.  From  sixteen  kilograms  of  one 
cheese,  I  obtained  about  0.5  gram  of  the  poison,  and  in  this 
case  the  individual  crystals  were  plainly  visible  to  the 
unaided  eye.  From  the  same  amount  of  another  cheese,  I 
obtained  only  about  0.1  gram,  and  the  crystals  in  this  case 
were  not  so  large.  I  have  no  idea,  however,  that  by  the 
method  used  all  the  poison  was  separated  from  the  cheese." 

To  this  ptomaine  Vaughan  has  given  the  name  tyro- 
\a<  toxicon  («t^  cheese,  and  -o-'/koc,  poison).  Its  chemistry 
will  be  discussed  in  a  subsequent  chapter. 

During  1887,  Wallace  found  tyrotoxicon  in  two 
samples  of  cheese  which  had  caused  serious  illness.  The 
first  of  these  came  from  Jeanesville,  Pa.,  and  the  symptoms 
as  reported  to  Wallace  by  Doolittle,  who  had  charge 
of  the  cases,  were  as  follows:  "There  were  at  least  fifty 
persons  poisoned  by  this  cheese.  There  were  also  eight 
others  who  ate  of  the  cheese,  but  felt  no  unpleasant  effects ; 
whether  this  was  due  to  personal  idiosyncrasy,  or  to  an 
uneven  distribution  of  the  poison  throughout  the  cheese,  I 
am  unable  to  say. 

"  The  majority,  however,  comprising  fifty  or  sixty  per- 
sons, were  seized,  in  from  two  to  four  hours  after  eating  the 
cheese,  with  vertigo,  nausea,  vomiting,  and  severe  rigors, 
though  varying  in  their  order  of  appearance  and  in  severity 
in  different  cases.  The  vomiting  and  chills  were  the  most 
constant  and  severe  symptoms  in  all  the  cases,  and  were 


58  PTOMAINES. 

soon  followed  by  severe  pain  in  the  epigastric  region, 
cramps  in  the  feet  and  lower  limbs,  pnrging  and  griping 
pain  in  the  bowels,  a  sensation  of  numbness  or  pins  and 
needles,  especially  in  the  limbs,  and  lastly,  very  marked 
prostration,  amounting  almost  to  collapse  in  a  few  cases. 

"The  vomit  at  first  consisted  of  the  contents  of  the 
stomach,  and  had  a  strong  odor  of  cheese ;  afterward  it 
consisted  of  mucus,  bile,  and  in  three  or  four  of  the  severer 
cases  blood  was  mixed  with  the  mucus  in  small  quantities. 
Microscopic  examination  of  the  same  was  not  made,  but  to 
the  eye  it  appeared  as  such.  The  vomiting  and  diarrhoea 
lasted  from  two  to  twelve  hours ;  the  rigors  and  muscular 
cramps,  one  to  two  hours.  The  diarrhoeal  discharges,  at 
first  fsecal,  became  later  watery  and  light  colored.  No 
deaths  occurred,  and  for  the  most  part  the  effects  were 
transient,  and  all  that  remained  on  the  following  day  were 
the  prostration  and  numbness ;  the  latter  occurred  in  about 
one-half  the  cases,  and  disappeared  in  from  one  to  three 
days. 

"  Children,  as  a  rule,  seemed  to  suffer  less  than  adults, 
and,  of  course,  it  was  not  possible  to  elicit  as  definite  symp- 
toms from  them.  The  suddenness  of  the  attack  was 
remarked  by  all,  some  feeling  perfectly  well  until  the 
moment  of  attack.  Nor  did  the  symptoms  seem  to  be  in 
proportion  to  the  amount  of  cheese  taken ;  some  of  the 
severest  cases  declared  they  had  not  eaten  more  than  a  cubic 
inch  of  it.  One  of  the  severest  cases  was  about  six  and 
one-half  months  pregnant,  but  no  interference  with  preg- 
nancy occurred.  All  the  cheese  which  caused  the  sickness 
came  from  the  same  piece." 

The  second  sample  of  cheese  examined  by  Wallace 
came  from  Riverton,  N.  J.  This  outbreak  included  a 
smaller  number  of  persons,  all  of  whom  recovered. 


POISONOUS    CHEESE.  59 

Still  more  recently  Wolff  has  detected  tyrotoxicon  in 
cheese  which  poisoned  several  persons  at  Shamokin,  Pa. 
The  pores  of  this  cheese  were  found  filled  Avith  a  grayish- 
green  fungoid  growth,  though  it  is  not  supposed  that  this 
fungus  was  connected  in  any  way  with  the  poisonous  nature 
of  the  cheese.  Tests  were  made  for  mineral  poison  with 
negative  results,  after  which  tyrotoxicon  was  recognized 
both  by  chemical  and  physiological  tests.  "A  few  drops  of 
the  liquid  (extract),  placed  on  the  tongue  of  a  young  kitten, 
produced  prompt  emesis  and  numerous  watery  dejections 
with  evident  depression  and  malaise  of  the  animal.  A 
larger  cat  was  similarly  affected  by  it,  though  the  depression 
and  malaise  were  not  so  marked  nor  so  long  continued." 

Cheese  poisoning  caused  the  death  of  several  children  in 
the  neighborhood  of  Heiligenstadt,  in  1879,  and  there  were 
many  fatal  cases  from  the  same  cause  in  Pyrmont,  in  1878. 
Unfortunately  we  have  not  been  able  to  find  any  detailed 
account  of  either  the  symptoms  or  the  post-mortem  appear- 
ances in  these  cases. 

Ehrhart  has  recently  published  the  history  of  some 
cases  of  poisoning  from  cheese,  of  which  the  following  is  an 
abstract :  The  family  of  a  workman,  consisting  of  eight 
persons,  ate  for  supper  600  grams  (about  eighteen  ounces) 
of  Limburger  cheese.  The  rind  was  covered  with  a  heavy 
mould,  while  the  interior  had  become  fluid  from  putrefac- 
tion, and  was  of  bitter  taste.  Three  ate  only  of  the  mouldy 
rind,  and  these  remained  well.  The  next  morning,  the  five 
who  had  eaten  of  the  inner  portion  suffered  from  vertigo, 
uausea,  vomiting,  and  abdominal  pains;  no  stool.  The 
father  had  convulsive  movements  of  all  the  extremities. 
The  pupils  were  dilated,  and  did  not  respond  to  light ;  there 
were  double  vision,  cold  sweat,  skin  cyanotic,  abdomen  dis- 
tended, difficulty  in   swallowing,   delirium,  mild   trismus, 


60  PTOMAINES. 

and  temperature  iO°  C.  (104^  F.).  The  temperature  of 
the  mother,  on  account  of  the  great  collapse,  was  subnormal. 
She  had  no  convulsive  movements,  but  there  was  prolonged 
loss  of  consciousness.  The  pulse  was  small  and  thready, 
and  threatened  paralysis  of  the  heart.  Recovery  was  very 
slow.  The  others  suffered  only  from  gastro-enteric  symp- 
toms. Ehehart  discusses  the  question  as  to  whether  these 
symptoms  were  due  to  tyrotoxicon,  or  to  infection  wdth 
microorganisms ;  but  as  we  have  not  had  access  to  his 
original  paper,  we  do  not  know  what  his  conclusions  are. 
However,  there  cannot  be  much  doubt  that  in  those  cases 
in  which  the  organism  is  taken  into  the  alimentary  canal, 
it  continues  the  elaboration  of  its  poisonous  products. 

Poisoxous  Milk. — In  1885  Vaughan  found  tyrotoxi- 
con in  milk  which  had  stood  in  a  well-stoppered  bottle  for 
about  six  months.  It  was  presumed  that  this  milk  was, 
when  first  obtained,  normal  in  composition,  but  since  this 
was  not  known  with  certainty,  the  following  experiments 
were  made  :  Several  gallon  bottles  were  filled  with  normal 
milk,  tightly  closed  with  glass  stoppers,  and  allowed  to 
stand  at  the  ordinary  temperature  of  the  room.  From  time 
to  time  a  bottle  was  opened  and  the  test  for  tyrotoxicon  was 
made.  These  tests  were  followed  by  negative  results  until 
about  three  months  after  the  experiment  was  begun.  Then 
the  poison  was  obtained  from  one  of  the  bottles.  The  coagu- 
lated milk  was  filtered  through  paper.  The  filtrate,  which 
was  colorless  and  decidedly  acid  in  reaction,  was  rendered 
feebly  alkaline  by  the  addition  of  potassium  hydrate  and 
agitated  with  ether.  After  separation,  the  ethereal  layer 
was  removed  with  a  pipette,  passed  through  a  dry  filter 
paper  in  order  to  remove  a  flocculent,  white  substance  which 
floated  in  it,  and  then  allowed  to  evaporate  spontaneously. 


POISOXOUS    MILK.  61 

If  necessary,  this  residue  was  dissolved  in  water  and  again 
extracted  with  ether.  As  tlie  ether  takes  up  some  water, 
there  is  usually  enough  of  the  latter  left  after  the  sponta- 
neous evaporation  of  the  ether  to  hold  the  poison  in  solu- 
tion, and  in  order  to  obtain  the  crystals  this  aqueous  solution 
must  be  allowed  to  stand  for  some  hours  in  vacuo  over 
sulphuric  acid. 

From  one-half  gallon  of  the  milk  there  was  obtained 
quite  a  concentrated  aqueous  solution  of  the  poison  after 
the  spontaneous  evaporation  of  the  ether.  Ten  drops  of 
this  solution  placed  in  the  mouth  of  a  small  dog  three 
weeks  old,  caused  within  a  few  minutes  frothing  at  the 
mouth,  retching,  the  vomiting  of  frothy  fluid,  muscular 
spasm  over  the  abdomen,  and  after  some  hours  watery 
stools.  The  next  day  the  dog  seemed  to  have  partially 
recovered,  but  was  unable  to  retain  any  food.  This  condi- 
tion continuing  for  two  or  three  days  the  animal  was  killed 
with  chloroform.  Xo  examination  of  the  stomach  was 
made. 

In  1886  Xewtox  and  Wallace  obtained  tyrotoxicon 
from  milk,  and  studied  the  conditions  under  which  it  forms. 
Their  report  is  of  so  much  value  that  the  greater  part  of  it 
is  herewith  inserted. 

"  On  August  7th  twenty-four  persons,  at  one  of  the  hotels 
at  Long  Branch,  were  taken  ill  soon  after  supper.  At 
another  hotel,  on  the  same  evening,  nineteen  persons  were 
seized  with  the  same  form  of  sickness.  From  one  to  four 
hours  elapsed  between  tiie  meal  and  the  first  symptoms. 
The  symptoms  noticed  were  those  of  gastro-intestinal  irri- 
tation, similar  to  poisoning  by  any  irritating  material — that 
is,  nausea,  vomiting,  cramps,  and  collapse ;  a  few  had  diar- 
rhoea. Dryness  of  the  throat  and  a  burning  sensation  in 
the  oesophagus  were  prominent  symptoms. 

6 


62  PTOMAINES. 

"  While  the  cause  of  the  sickness  was  being  sought  for, 
and  one  week  after  the  first  series  of  cases,  thirty  persons  at 
another  hotel  were  taken  ill  with  precisely  the  same  symp- 
toms as  noticed  in  the  first  outbreak. 

"  When  the  news  of  the  outbreak  was  published  one  of 
us  immediately  set  to  work,  under  the  authority  of  the  State 
Board  of  Health,  to  ascertain  the  cause  of  the  illness.  The 
course  of  the  investigation  was  about  as  follows  : 

"  The  character  of  the  illness  iudicated,  of  course,  that 
some  article  of  food  was  the  cause,  and  the  first  part  of  our 
task  was  to  single  out  the  one  substance  that  seemed  at 
fault.  The  cooking  utensils  were  also  suspected,  because 
unclean  copper  vessels  have  often  caused  irritant  poisoning. 
Articles  of  food,  such  as  lobsters,  crabs,  blue  fish,  and  Spanish 
mackerel,  all  of  which  at  times,  and  with  some  persons  very 
susceptible  to  gastric  irritation  have  produced  toxic  symp- 
toms, were  looked  for,  but  it  was  found  that  none  of  these 
had  been  eaten  at  the  time  of  the  outbreak.  The  cooking 
vessels  were  examined,  and  all  were  found  clean  and  bright, 
and  no  evidence  of  corrosion  was  presented. 

"Further  inquiry  revealed  the  fact  that  all  who  had  been 
taken  ill  had  ased  milk  in  greater  or  less  quantities,  and 
that  persons  who  had  not  partaken  of  milk  escaped  entirely ; 
corroborative  of  this,  it  was  ascertained  that  those  who  had 
used  milk  to  the  exclusion  of  all  other  food  were  violently 
ill.  This  was  prominently  noticed  in  the  cases  of  infants 
fed  from  the  bottle,  when  nothing  but  uncooked  milk  was 
used.  In  one  case  an  adult  drank  about  a  quart  of  the 
milk,  and  was  almost  immediately  seized  with  violent  vom- 
iting followed  by  diarrhoea,  and  this  by  collapse.  Suffice 
it  to  say,  that  we  were  able  to  eliminate  all  other  articles  of 
food  and  to  decide  that  the  milk  was  the  sole  cause  of  the 
outbreak. 


POISONOUS    MILK.  63 

"  Having  been  able  to  determine  this,  tlie  next  step  was 
to  discover  why  that  article  should,  in  these  cases,  cause  so 
serious  a  form  of  sickness. 

"The  probable  causes  which  we  were  to  investigate  were 
outlined  as  follows:  (1)  Some  chemical  substance,  such  as 
borax,  boric  acid,  salicylic  acid,  sodium  bicarbonate,  sodium 
sulphate,  added  to  preserve  the  milk  or  to  correct  acidity. 
(2)  The  use  of  polluted  water  as  an  adulterant.  (3)  Some 
poisonous  material  accidentally  present  in  the  milk.  (4) 
The  use  of  milk  from  diseased  cattle.  (5)  Improper  feed- 
ing of  the  cattle.  (6)  The  improper  care  of  the  milk.  (7) 
The  development  in  the  milk  of  some  ferment  or  ptomaine, 
such  as  tyrotoxicon. 

"At  the  time  of  the  first  outbreak  we  were  unable,  unfor- 
tunately, to  obtain  any  of  the  noxious  milk,  as  that  uncon- 
sumed  had  been  destroyed ;  but  at  the  second  outbreak  a 
liberal  quantity  was  procured. 

"  It  was  soon  ascertained  that  one  dealer  had  supplied  all 
the  milk  used  at  the  three  hotels  where  the  cases  of  sickness 
had  occurred.  His  name  and  address  having  l)een  obtained, 
the  next  step  in  the  investigation  was  to  inspect  all  the 
farms,  and  the  cattle  thereon,  from  which  the  milk  was 
taken.  We  also  learned  that  two  deliveries  at  the  hotels 
were  made  daily,  one  in  the  morning  and  one  in  the  even- 
ing ;  that  the  milk  supplied  at  night  was  the  sole  cause  of 
sickness,  and  that  the  milk  from  but  one  of  the  farms  was 
at  fault.  The  cows  on  this  farm  were  found  to  be  in  good 
health,  and,  besides  being  at  pasture,  were  well  fed  with 
bran,  middlings,  and  corn-meal. 

"So  far  we  had  been  able  to  eliminate  as  causes  diseased 
cattle  and  improper  feeding,  and  we  were  then  compelled 
to  consider  the  other  possible  sources  of  the  toxic  material. 

"  While  the  inspection  of  the  farms  was  being  made,  the 


6-1  PTOMAINES. 

analysis  of  the  milk  was  in  progress.  The  results  of  this 
showed  that  no  chemical  substance  had  been  added  to  the 
milk,  that  it  was  of  average  composition,  that  no  polluted 
water  had  been  used  as  a  diluent,  and  that  no  poisonous 
metals  were  present.  This  result  left  us  nothing  to  con- 
sider but  two  probable  causes  :  improper  care  of  the  milk, 
and  the  presence  of  a  ferment. 

"As  to  the  former,  we  soon  learned  much.  The  cows 
were  milked  at  the  unusual  and  abnormal  hours  of  mid- 
night and  noon,  and  the  noon's  milking — that  which  alone 
was  followed  by  illness — was  placed  while  hot,  in  the  cans, 
and  then,  without  any  attempt  at  cooling,  carted  eight  miles 
during  the  warmest  part  of  the  day  in  a  very  hot  month. 

"This  practice  seemed  to  us  sufficient  to  make  the  milk 
unpalatable,  if  not  injurious,  for  it  is  M'ell  known  that  when 
fresh  milk  is  closed  up  in  a  tight  vessel  and  then  deposited 
in  a  warm  place,  a  very  disagreeable  odor  and  taste  are 
developed.  Old  dairymen  speak  of  the  animal  heat  as  an 
entity,  the  removal  of  which  is  necessary  in  order  that  the 
milk  shall  keep  well  and  have  a  pleasant  taste.  While  we 
do  not  give  this  thing  a  name,  we  are  fully  convinced  that 
milk  should  be  thoroughly  cured  by  proper  chilling  and 
aeration  before  it  is  transported  any  distance  or  sold  for 
consumption  in  towns  or  cities. 

"  This  opinion  is  based  on  a  study  of  the  methods  prev- 
alent among  experienced  dairymen,  who  ship  large  quanti- 
ties of  milk  to  our  great  cities.  The  usual  practice  is  to 
allow  the  milk  to  stand  in  open  vessels,  surrounded  by  ice 
or  cold  water,  for  from  eight  to  twelve  hours  before  trans- 
portation, and  when  placed  on  the  cars  it  has  a  temperature 
of  from  50°  to  60°  F.,  and  is  delivered  to  consumers  in  a 
perfectly  sweet  condition.  The  city  of  New  York  receives 
about   200,000   gallons   each   day  from  the  surrounding 


POISOXOUS    MILK.  65 

country,  anrl  much  of  it  brought  iu  hy  the  railroads  has 
beeu  ou  the  c-ars  for  a  time  varying  from  six  to  twelve 
hours,  yet  we  seldom  hear  of  any  of  this  milk  undergoing 
the  peculiar  form  of  fermentation  set  up  in  the  Long 
Branch  milk.  We  may  account  for  this  by  assuming  that 
the  proper  care  of  the  milk  after  it  was  taken  from  the 
cow,  and  the  low  temperature  at  which  it  was  kept,  have 
prevented  the  formation  of  any  ferment ;  this  opinion 
seems  to  be  endorsed  by  all  dairymen  and  managers  of 
large  creameries  with  whom  we  have  consulted.  They  all 
agree  in  stating  that  milk  maintained  at  a  low  temperature 
can  be  kept  sweet  and  in  good  condition  for  many  days. 

"We  have  dwelt  on  this  branch  of  our  topic  somewhat 
extensively,  because  we  are  fully  persuaded  that  the  im- 
proper care  of  the  milk  had  much  to  do  with  the  illness  it 
produced. 

"  The  results  of  our  inquiry  having  revealed  so  much, 
we  next  attempted  to  isolate  some  substance  from  the 
poisonous  milk,  in  order  that  the  proof  might  be  more 
evident.  A  quantity  of  the  milk  that  had  caused  sickness 
in  the  second  outbreak  was  allowed  to  coagulate,  was  then 
thrown  on  a  coarse  filter,  and  the  filtrate  collected.  This 
latter  was  highly  acid,  and  was  made  slightly  alkaline  by 
the  addition  of  potassium  hydrate.  This  alkaline  filtrate 
was  now  agitated  with  an  equal  volume  of  pure,  dry  ether, 
and  allowed  to  stand  for  several  hours,  when  the  ethereal 
layer  was  drawn  off  by  means  of  a  pipette.  Fresh  ether 
was  added  to  the  residuum,  then  agitated,  and,  when  sepa- 
rated, was  drawn  off  and  added  to  the  first  ethereal 
extract.  This  was  now  allowed  to  evaporate  spontaneously, 
and  the  residue,  which  seemed  to  contain  a  small  amount 
of  fat,  was  treated  with  distilled  water  and  filtered,  the 
filtrate  treated  with  ether,  the  ethereal  solution  drawn  off 

6* 


66  PTOMAINES. 

and  allowed  to  evaporate,  when  we  obtained  a  mass  of 
needle-shaped  crystals.  This  crystalline  substance  gave  a 
blue  color  with  potassium  ferricyauide  and  ferric  chloride, 
and  reduced  iodic  acid.  The  crystals,  when  placed  on  the 
tongue,  gave  a  burning  sensation.  A  portion  of  the  crystals 
was  mixed  with  milk  and  fed  to  a  cat,  when,  in  the  course 
of  half  an  hour,  the  animal  was  seized  with  retching  and 
vomiting,  and  was  soon  in  a  condition  of  collapse,  from 
which  it  recovered  in  a  few  hours. 

"We  are  justified  in  assuming,  after  weighing  well  all 
the  facts  ascertained  in  the  investigation,  that  the  sickness 
at  Long  Branch  was  caused  by  poisonous  milk,  and  that 
the  toxic  material  was  tyrotoxicon. 

"  The  production  of  this  substance  was  no  doubt  due  to 
the  improper  management  of  the  milk — that  is,  too  long  a 
time  was  allowed  to  elapse  between  the  milking  and  the 
cooling  of  the  milk,  the  latter  not  being  attended  to  until 
the  milk  was  delivered  to  the  hotel ;  whereas,  if  the  milk 
had  been  cooled  immediately  after  it  was  drawn  from  the 
cows,  fermentation  would  not  have  ensued,  and  the  resulting 
material,  tyrotoxicon,  would  not  have  been  produced." 

In  the  same  year,  Schearer  found  the  same  poison  in 
the  milk  used  by,  and  the  vomited  matter  of,  persons  made 
sick  at  a  hotel  at  Corning,  Iowa. 

In  1887,  Firth,  an  English  army  surgeon  stationed  in 
India,  reported  an  outbreak  of  milk  poisoning  among  the 
soldiers  of  his  garrison.  From  the  milk  he  separated,  by 
Vaughan's  method,  tyrotoxicon.  He  also  obtained  tyro- 
toxicon from  milk  which  had  been  kept  for  some  months 
in  stoppered  bottles,  as  had  been  previously  done  by 
Vaughan.    (See  page  60.) 

In  1887,  Mesic  and  Vaughan  observed  four  cases  of 
milk  poisoning,  three  of  Avhich  terminated  fatally,  and 


POISONOUS    MILK.  67 

NovY  and  Vaugiian  obtained  tyrotoxicon  from  tlie  milk, 
and  from  the  contents  of  the  intestine  in  one  of  the  fatal 
cases.     Vaughan  reports  these  cases  as  follows  : 

"  September  23,  1887,  I  was  visited  by  Dr.  A.  G.  Mesic, 
of  Milan,  Michigan,  who  informed  me  that  he  had  four 
members  of  a  family  under  his  charge,  all  of  whom  were 
seriously  ill  with  peculiar  symptoms  which  he  believed  to 
be  caused  by  tyrotoxicon.  Since  Dr.  Mesic  has  written 
out  for  me  the  history  of  these  cases,  I  will  insert  his  report 
in  full,  as  follows  : 

"  '  Saturday,  September  17,  while  passing  the  residence 
of  S.  H.  Evans,  a  respectable  farmer,  I  was  called  in  to  see 
him.  I  found  him — a  man  of  about  fifty  years,  spare 
and  muscular — vomiting  severely,  with  flushed  face,  but 
with  a  temperature  of  9G°  F.  There  was  marked  throb- 
bing of  the  abdominal  aorta ;  the  tongue  had  a  white, 
heavy  coating,  and  the  breathing  was  very  labored.  I  set 
to  work  with  the  ordinary  remedies  to  allay  the  vomiting, 
which  had  already  continued  for  some  hours.  The  vomited 
matters  were  colored  with  bile.  Pupils  were  dilated,  and 
a  rash  resembling  that  of  scarlatina,  but  coarser,  covered 
the  chest,  forearms,  and  legs  below  the  knees,  while  the 
abdomen  and  thighs  remained  unaffected.  As  the  bowels 
had  not  been  moved  since  the  beginning  of  the  attack,  I 
administered  a  purgative  dose  of  calomel  with  a  little  podo- 
phyllin  and  rhubarb.  On  Sunday  a  small  stool  resulted. 
During  that  day  and  night,  and  the  following  day,  the 
retching  and  vomiting  continued.  Small  doses  of  carbolic 
acid  seemed  to  give  the  most  relief.  After  the  movement 
of  the  bowels  the  symptoms  were  somewhat  more  prom- 
ising ;  but  a  heavy  and  unfavorable  stupor  was  observable 
and  persistent. 

"  '  On  Sunday  the  coating  of  the  tongue  remained  very 


6S  PTOMAINES. 

thick,  and  had  changed  to  a  dark  brown  color.  At  first  I 
thought  that  his  symptoms  indicated  a  depressed  condition, 
which  I  had  known  in  one  instance  to  precede  typhoid 
fever.  However,  after  a  few  days,  I  concluded  that  I 
must  look  for  the  cause  of  the  condition  among  the  poi- 
sons ;  but  I  could  think  of  no  one  poison  which  would  be 
likely  to  produce  all  the  symptoms  observed.  During 
Monday,  Tuesday,  and  Wednesday,  there  was  but  little 
change,  and  the  treatment  was  continued. 

"  '  On  Thursday  morning  I  found  the  son  Arthur,  a  lad 
of  eighteen  years,  strong  and  vigorous,  suffering  with  the 
same  symptoms,  only  in  a  more  violent  form.  After 
supper  on  Wednesday  evening,  he  was  taken  with  nausea 
and  vomiting.  He  had  no  rash,  but  the  symptoms  were 
otherwise  identical  with  those  of  the  father,  except  in  being 
more  severe.     I  gave  a"  cathartic,  which  acted  only  slightly. 

"^At  my  evening  visit  I  found  Mrs.  Evans,  a  lady  of 
about  forty-five,  previously  in  good  health,  with  the  same 
symj)toms.  In  this  case  the  stupor  was  more  marked  from 
the  first.  I  was  unable  at  any  time  to  obtain  any  cathartic 
action  in  this  case.  Copious  enemata  of  warm  water  were 
used,  but  succeeded  only  in  washing  some  hardened  lumps 
from  the  rectum.  By  this  time  I  had  concluded  that  the 
poison  was  most  likely  tyrotoxicon. 

"  '  On  Friday  morning  the  only  remaining  member  of 
the  family  at  home,  Miss  Alma,  sixteen  years  of  age,  was 
affected  in  the  same  way  as  the  others.  On  that  day  I 
went  to  Ann  Arbor,  and  gave  a  history  of  the  cases  so  far 
to  Dr.  Yaughan,  who,  from  the  symptoms,  thought  that 
my  diagnosis  was  most  probably  correct,  and  he  advised 
with  me  as  to  treatment,  which  I  carried  out.  I  gave  two 
grains  of  sodium  salicylate  every  four  hours,  and  used  small 
doses  of  the  tonics  and  stimulants,  quinine,  nux  vomica, 


POISONOUS     MILK.  69 

cUfritalls,  whiskey,  and  tlie  aromatic  spirits  of  ammonia. 
On  Saturday  the  symptoms  in  all  remained  unimproved, 
and  in  the  mother  and  son  the  stupor  and  labored  breath- 
ino;  grew  more  marked. 

"  '  On  Sunday,  I  again  went  to  Ann  Arbor,  and  brought 
Dr.  Vaughan  with  me  to  see  the  patients.  The  tempera- 
ture of  the  mother  on  Sunday  was  as  low  as  9-1°,  and  that 
of  the  son  95°.  Dr.  Vaughan  agreed  with  me  as  to  diag- 
nosis and  treatment.  Sunday  evening,  the  patients  were 
all  removed  to  the  house  of  a  neighbor,  about  forty  rods 
distant  (the  reasons  for  this  will  be  given  later).  Dr. 
Vaughan  and  I  both  expressed  the  fear  that  the  mother, 
and  possibly  the  son,  would  not  live  through  the  night. 
Both  of  these  rapidly  grew  worse,  and  the  son  died  at  7.45 
A.M.,  and  the  mother  at  4  p.m.,  Monday. 

"  '  During  Monday  the  daughter  rapidly  grew  worse,  and 
at  the  time  of  her  mother's  death  could  not  be  aroused,  and 
practically  she  remained  unconscious  from  that  time  on. 
The  father  was  very  weak,  but  retained  his  consciousness 
all  the  time.  Convulsive  movements  of  the  limbs  had 
been  noticed  in  the  son,  but  not  in  the  mother.  These 
now  became  more  marked  in  the  daughter,  who  remained 
in  the  heavy  stupor,  with  labored  breathing,  until  5  p.m. 
Thursday,  when  she  died. 

"^Mr.  Evans  has  slowly  improved,  and  now,  October 
18th,  is  able  to  walk  about  the  room.  The  sodium  sali- 
cylate, even  in  the  small  doses  used,  seemed  to  cause  severe 
headache  ;  so  apparent  was  this  that  the  drug  was  discon- 
tinued, and  drop  doses  of  amyl  nitrite,  given  every  hour, 
seemed  to  relieve  the  pain  in  the  head.  The  father's  tem- 
perature remained  below  the  normal  until  Thursday,  Octo- 
ber 14th,  when   it  reached  the  normal.     After  this  it  was 


70  PTOMAINES. 

found  ouce  as  high  as  99.5°,  then  99°  F.,  then  again  normal, 
where  it  remains. 

"  'AH  complained  of  a  burning  constriction  in  the  throat, 
and  difficulty  in  swallowing,  and  all,  as  long  as  they  were 
conscious,  frequently  called  for  ice.  In  all  the  pulse  was 
rapid  and  feeble,  and  death  seemed  to  result  from  failure 
of  the  heart.  Those  who  died  voided  urine  involuntarily, 
while  Mr.  Evans  passed  small  quantities  frequently,  and 
for  this  buchu  and  uva  ursa  were  given.  During  his  con- 
valescence small  doses  of  morphine  were  given  to  the 
father,  as  he  was  unable  to  sleep,  and  became  very  rest- 
less. He  is  now  taking  teaspoonful  doses  of  the  elixir  of 
calisaya  and  iron  every  four  hours.' 

"As  stated  above  by  Dr.  Mesic,  I  first  saw  these  patients 
Sunday,  September  25th.  On  a  sofa  in  the  room  we  found 
the  daughter.  Alma.  She  had  been  vomiting  during  the 
day,  and  seemed  much  exhausted.  She  was  not  inclined  to 
talk,  and  seemed  to  be  in  a  stupor,  though  when  spoken  to 
she  responded  rationally.  Her  pupils  were  slightly  dilated, 
her  tongue  coated,  her  pulse  120  and  weak,  her  face  flushed, 
and  a  violent  throbbing  could  be  felt  over  the  abdomen, 
which  was  retracted.     Her  temperature  was  96°  F. 

"  In  another  room  were  the  father,  mother,  and  son,  two 
of  them  dying.  The  father  was  rational,  and  talked  with 
some  freedom  when  I  asked  as  to  the  kind  of  food  they 
had  been  eating,  etc.  His  pupils  were  normal.  His  face 
could  not  be  said  to  present  any  peculiar  feature.  His 
pulse  was  rapid,  breathing  somewhat  labored,  and  the 
throbbing  of  the  abdominal  aorta  was  plainly  felt.  The 
abdomen  was  retracted,  and  there  \vas  no  pain  on  pressure. 
He  complained  of  a  burning  constriction  of  the  throat, 
swallowed  with  difficulty,  and  said  that  his  throat  and 
stomach  felt  as  though  they  were  on  fire. 


POISONOUS    MILK.  71 

"The  mother  lay  perfectly  still  with  eyelids  closed,  as  if 
iu  a  deep  sleep.  Her  pulse  was  rapid,  her  face  had  a  livid 
flush,  her  breathing  was  about  35  per  minute,  and  labored. 
The  skin  was  cool,  but  neither  abnormally  moist  nor  speci- 
ally dry  and  harsh.  Siie  could  uot  be  aroused.  In  fact, 
she  was  comatose. 

"  The  son  rolled  uneasily  from  one  side  of  the  bed  to  the 
other.  His  breathing,  also,  was  very  labored.  His  eyelids 
were  closed,  and  the  pupils  were  markedly  dilated — did  not 
respond  to  light.  He  could  not  be  aroused.  In  mother 
and  son,  as  well  as  in  father  and  daughter,  the  abdomen 
was  retracted,  and  the  throbbing  of  the  abdominal  aorta 
was  easily  felt. 

"Now,  to  what  were  these  symptoms  due?  They  were 
certainly  those  of  some  poison.  Dr.  Mesic  had  brought 
me  some  of  the  vomited  matter,  which  I  tested  thoroughly 
for  mineral  poisons,  with  negative  results.  The  symptoms 
certainly  were  not  those  of  morphine,  strychnine,  digitalis, 
or  aconite.  They  did  have  some  resemblance  to  those  of 
belladonna,  but  yet  they  were  not  the  symptoms  of  bella- 
donna. The  pupils  were  not  as  widely  dilated  as  they 
would  be  in  belladonna  poisoning.  There  was  in  none  of 
these  persons  the  active  delirium  of  belladonna  poisoning. 
There  was  no  picking  at  the  clothing,  no  grasping  of  imag- 
inary objects  in  the  air,  no  hallucinations  of  vision.  Surely 
it  could  uot  be  any  vegetable  alkaloid  with  which  I  was 
familiar. 

"On  tlie  other  hand,  we  know  that  nausea,  vomiting, 
headache,  dilatation  of  the  pupil,  rapid  pulse,  heavy  breath- 
ing, constipation,  and  great  prostration,  with  stupor,  do 
occur  iu  cases  of  poisoning  with  certain  ptomaines.  There- 
fore we  beo;an  to  look  for  conditions  which  would  be  favor- 


72  PTOMAINES. 

able  for  the  production  of  putrefactive  alkaloids.  These 
couditious  we  were  not  long  in  finding. 

"The  family,  which  consisted  of  the  four  persons  sick,  and 
of  a  daughter  about  twenty  years  of  age,  who  was  away 
from  home  at  the  time  when  the  others  were  taken  ill, 
and  for  some  mouths  before  that  time,  was  evidently  a 
tidy  one.  This  was  shown  by  their  personal  appear- 
ance, and  by  the  clothing  and  bedding.  But  the  house 
in  which  they  lived  was  very  old,  and  very  much 
decayed.  Mr.  Ev^ans  had  purchased  the  farm  six  years 
ago ;  and  for  some  three  years  past,  at  least,  they  had  beeu 
troubled  every  now  and  then,  one  or  more  of  the  family, 
with  nausea  and  vomiting,  followed  by  more  or  less  prostra- 
tion. But  in  no  instance,  up  to  the  present  illness,  had  the 
symptoms  been  sufficient  to  cause  them  to  summon  a  physi- 
cian. The  family  had  worked  hard  in  order  to  pay  for  the 
farm,  and  had  determined  to  make  the  old  house  do  until 
they  were  out  of  debt.  Even  before  this  family  had  moved 
to  the  farm,  the  house  had  been  known  among  the  neigh- 
bors as  an  unhealthy  one,  and  there  had  beeu  much  sick- 
ness and  a  number  of  deaths  among  its  former  tenants. 

"  The  house  is  a  frame  one,  and  one  of  the  neighbors  said 
to  me  that  it  was  an  old  house  when  he  came  to  the  neigh- 
borhood thirty-seven  years  ago.  It  consists  of  two  rooms 
on  the  ground-floor,  with  attic  rooms  above.  The  frame 
rests  upon  four  large  logs  or  sills,  which  lie  directly  upon 
the  ground,  and  are  thoroughly  rotten.  There  is  no  cellar 
under  any  part  of  the  house.  From  the  front,  at  least,  the 
surface  sIojdcs  toward  the  house,  and  the  rain  water  runs 
under  it.  In  the  floor  of  one  room  a  trap  door  had  been 
placed,  and  directly  under  this  a  small  excavation  had  been 
made  for  the  purpose  of  collecting  the  rain  water  when  it 
accumulated  under  the  house.     Although  this  pit  was  dry 


POISONOUS    MILK.  73 

at  the  time  of  our  examiuation,  its  sides  and  bottom  were 
marked  with  cray-fish  holes,  showinu'  that  water  had  stood 
in  it.  The  floor  was  laid  of  unjointed  boards,  and  every 
time  that  it  was  swe})t  much  of  the  tilth  fell  through  the 
cracks,  and  every  time  that  the  tidy  housewife  scoured  and 
mopped  the  floor,  the  water,  carrying  with  it  the  filth,  ran 
through  the  crevices,  and  thus  the  conditions  most  favorable 
for  putrefactive  changes  were  brought  into  existence  and 
maintained. 

"  One  corner  of  one  of  the  rooms  had  been  transformed 
into  a  small  room,  or  buttery,  as  it  was  called,  and  in  this, 
on  shelves,  the  food  was  kept.  On  account  of  the  more 
frequent  scouring  demanded  by  that  part  of  the  floor 
enclosed  in  this  buttery,  the  boards  had  rotted  away,  and  a 
second  layer  of  boards  had  been  placed  over  the  original 
floor.  Between  these  two  floors  we  found  a  great  mass  of 
moist,  decomposing  matter,  the  accumulations  of  years, 
which  the  broom  could  not  reach.  When  this  floor  was 
taken  up,  a  peculiar,  nauseating  odor  was  observable,  and 
was  sufficient  to  produce  nausea  and  vomiting  in  one  of  the 
persons  engaged  in  the  examination.  Some  of  the  dirt 
from  beneath  the  floor,  and  some  of  that  which  had  accumu- 
lated between  the  boards  in  the  buttery,  were  taken  for 
further  study. 

"  The  condition  of  the  house  was  supposed  to  be  unfavor- 
able to  the  patients,  and  for  this  reason  they  were  moved, 
as  Dr.  Mesic  has  stated,  to  the  house  of  a  neighbor.  Of 
course,  thorough  examination  of  the  house  was  not  made 
until  the  patients  had  been  removed. 

"Special  inquiry  was  now  made  concerning  the  food  used 
by  this  family.  They  had  been  living  very  simply.  They 
lived  upon  bread,  butter,  milk,  and  potatoes,  with  coffee 
and  ripe  fruit.    They  had  eaten  no  canned  foods  for  months. 

7 


74  PTOMAINES. 

They  ate  but  little  meat.  Occasionally  a  chicken  was  killed 
and  served,  and  rarely,  some  fresh  meat  was  obtained  from 
the  village.  During  the  week  in  which  they  were  taken  ill, 
all  the  meat  used  consisted  of  slices  from  a  piece  of  bacon, 
the  only  meat  which  was  kept  in  the  house,  and  a  chicken. 
None  of  the  latter  remained,  but  the  bacon  was  examined. 
It  seemed  in  perfect  condition,  and  contained  no  trichinae. 
Moreover,  as  has  been  seen  from  the  history  of  the  cases, 
all  the  members  of  the  family  were  not  made  sick  by  any 
one  meal,  but  the  opportunity  of  obtaining  the  poison  must 
have  been  present  for  some  time.  Moreover,  the  fact  that 
previous  similar,  but  less  severe,  attacks  had  occurred  at 
intervals  for  the  past  three  years,  convinced  us  that  the 
poison  must  owe  its  origin  to  some  long-existing  condition. 

"  The  drinking  water  supply  was  also  inv^estigated.  The 
water  was  obtained  from  a  shallow  well,  and  some  of  it  was 
taken  for  analysis.  But  several  families  had  for  years  used 
water  from  this  well,  and  had  remained  healthy. 

"  The  milk  nsed  by  the  family  was  studied.  Of  course, 
we  could  get  none  of  that  which  had  been  used  before  the 
members  of  the  family  were  stricken  down.  As  soon  as  he 
made  the  diagnosis  of  tyrotoxicon  poisoning.  Dr.  Mesic 
ordered  the  discontinuance  of  the  use  of  milk,  not  only  with 
the  sick,  but  he  forbade  the  daughter,  who  had  returned, 
and  any  of  the  visitors  using  it.  Mr.  Evans  owned  four 
milch  cows,  and  they  were  supplied  with  fair  pasturage  and 
abundant  water.  The  greater  part  of  the  milk  was  placed 
in  tin  cans  which  were  set  in  a  wooden  trough  in  the  yard, 
and  surrounded  by  cold  water.  The  covers  to  the  cans 
were  arranged  so  that  the  air  could  have  free  access  to  the 
milk,  and  were  left  in  this  position  until  the  milk  was 
thoroughly  cooled.  Indeed,  the  cans  were  furnished  by  a 
creamery  company,  which  followed  the  directions  which  I 


POISONOUS     MILK.  75 

have  previously  given  for  tlie  care  of  milk.  On  his  first 
visit  to  me,  Dr.  Mesic  brought  some  of  the  milk  from  one 
of  the.se  cans.  This  I  examined,  but  failed  to  find  tyro- 
toxieon  in  it. 

"  However,  the  family  did  not  drink  any  of  the  milk  from 
the  cans.  That  which  they  did  use  was  kept  in  the  buttery 
which  I  have  described.  Here  it  stood  upon  a  shelf,  and 
some  members  of  the  flimily,  at  least,  were  in  the  habit  of 
drinking  from  it  between  meals.  This  was  especially  true, 
it  is  said,  of  the  son.  He  would  frequently  com£  from  his 
work  in  the  fields,  go  into  the  buttery  and  drink  a  gla.ss  or 
more  of  the  milk.  Mr.  Evans  states  that  he  frequently 
observed  that  the  taste  of  the  milk  was  not  pleasant.  On 
my  first  visit  to  the  premises,  I  advised  that  some  of  the 
milk  should  be  taken  from  the  cans,  alloM-ed  to  .stand  in  the 
buttery  over  niglit,  and  be  sent  to  me  the  next  day.  This 
was  done,  and  in  this  milk  we  found  tyrotoxicon,  not  only 
by  the  employment  of  chemical  tests,  but  by  j)oisoning  a 
kitten  with  it. 

''  On  the  death  of  the  mother  and  son.  Dr.  Mesic  asked  for 
a  post  mortem,  but  the  friends  objected,  and  the  undertaker 
used  an  arsenical  embalming  fluid,  so  that,  although  consent 
was  suKsequently  oljtained,  it  was  decided  that  the  exami- 
nation would  be  so  vitiated  as  to  be  worthless.  On  the 
death  of  the  daughter,  the  coroner  summoned  a  jury,  and 
held  an  inquest.  The  post-mortem  was  conducted  by  Dr. 
George  A.  Hendricks,  in  the  presence  of  the  jury  and 
.several  physicians  who  had  been  invited.  Dr.  Hendricks 
has  kindly  furnished  me  with  his  report,  which  I  present 
here  in  full : 

"The  autopsy  was  held  fifteen  hours  after  death.  The 
abdominal  vi.scera  were  first  examined.  The  great  omen- 
tum  was  small,  in   normal  position,  covering  the  small 


76  PTOMAINES. 

intestine.  The  small  intestine  was  moderately  distended 
with  flatus.  The  jejunum  was  ashy-green  in  color;  the 
ileum  purplish-green.  About  eighteen  inches  from  the  ter- 
mination of  the  ileum  was  found  a  diverticulum  two  inches 
in  length.  The  small  intestine  contained  very  little  ali- 
mentary matter.  The  vermiform  appendix  was  free,  con- 
tained some  small  fecal  lumps,  and  showed  no  evidence  of 
inflammation.  The  csecum,  ascending,  transverse,  and 
descending  colon,  were  empty  and  their  circular  fibres  were 
tightly  copstricted,  except  at  intervals  where  the  intestine 
was  distended  with  gas.  The  sigmoid  flexure  was  moder- 
ately distended  with  gas,  and  the  rectum  contained  small 
bits  of  fecal  matter.  The  stomach  was  somewhat  contracted 
and  lay  wholly  upon  the  left  side  of  the  median  line.  It 
contained  a  few  ounces  of  fluid.  Its  extremities  were  ligated 
and  the  organ  removed.  The  mucous  membrane  of  the 
stomach  and  intestine  were  not  examined  until  they  reached 
the  chemist.  The  duodenum  was  distended  with  flatus. 
The  liver  was  normal  in  size  and  appearance.  The  gall- 
bladder contained  about  one  ounce  of  bile.  The  spleen  was 
normal.  One-half  ounce  of  fluid  deeply  stained  with  blood 
was  found  in  Douglas's  cul-de-sac.  The  uterus,  Fallopian 
tubes,  and  ovaries  were  deeply  congested.  The  left  ovary 
was  enlarged  and  presented  on  its  posterior  surface  a  hemor- 
rhagic spot,  oval,  about  one-half  line  in  length,  and  several 
other  less  distinct  ones.  The  right  ovary  was  normal  in 
size  and  showed  numerous  Graaffian  scars.  The  ureters  and 
bladder  were  normal ;  the  latter  contained  a  small  amount 
of  urine.  The  peritoneum,  pancreas,  and  kidneys  were 
perfectly  normal. 

"The  thoracic  cavity  was  next  opened.  The  lungs  were 
normal ;  there  was  about  one-half  ounce  of  free  serum  in 
the  left  pleural  cavity ;  none  in  the  right.     Pericardium 


POISONOUS    MILK.  77 

normal ;  riolit  auricle  in  diastole ;  left  auricle  and  both 
ventricles  in  systole. 

"The  dura  mater  showed  venous  congestion;  the  arach- 
noid normal ;  the  pia  mater  congested.  On  the  surface 
of  the  centrum  ovale,  small  drops  of  blood  oozed  from  the 
divided  vessels.  The  large  veins  of  the  velum  interpositum 
were  distended.  Third  and  fourth  ventricles  were  slightly 
distended  with  serous  fluid,  but  the  walls  were  normal. 
There  seemed  to  be  slight  softening  of  the  optic  thalami. 
The  sub-arachnoid  fluid  was  about  twice  the  normal  quan- 
tity. 

"  On  examination  of  the  mucous  membrane  of  the  stomach 
and  intestine  in  the  presence  of  the  chemist,  Prof.  A.  B, 
Prescott,  nothing  abnormal  could  be  found.  The  membrane 
was  stained  with  bile,  but  there  was  not  the  slightest  red- 
ness. The  solitary  glands  were  distinct,  but  not  at  all 
inflatned.     Peyer's  patches  were  normal. 

"  It  will  be  seen  that  there  existed  no  lesion  which  would 
account  for  the  death.  The  venous  congestion  observed  in 
the  brain  would  follow  from  failure  of  the  heart. 

"Some  of  the  post-mortem  appearances  bore  a  striking 
resemblance  to  those  which  I  had  observed  in  cats  poisoned 
with  tyrotoxicon.  This  was  especially  noticeable  in  the  con- 
dition of  the  mucous  membrane  of  the  stomach  and  intestine. 
Tyrotoxicon  produces  the  symptoms  of  a  gastro-intestinal 
irritant,  but  not  the  lesions.  The  contraction  of  the  circular 
fibres  of  the  intestine,  which  undoubtedly  caused  the  con- 
stipation, I  had  also  observed  in  cats  that  died  from  tyro- 
toxicon poi.soning  without  either  vomiting  or  stool.  The 
action  of  this  poison  upon  the  stomach  and  intestine  must 
be  through  the  nervous  system.  Small  doses  cause  both 
vomiting  and  purging,  while  after  large  doses  vomiting  may 
be  impossible,  and  obstinate  constipation  may  exist.     Both 

7* 


78  PTOMAINES. 

the  vomitiug  and  purging  after  small  doses  are  undoubt- 
edly due  in  part  to  increased  activity  of  the  circular  fibres 
of  the  muscular  coats,  induced  through  the  nerves;  and  the 
inability  to  vomit,  and  the  constipation,  one  or  both  of 
which  may  be  observed  after  large  doses  of  the  poison,  are 
due  to  spasm  of  the  same  muscles,  induced  in  the  same 
manner. 

"Prof  A.  B.  Prescott  was  requested  by  the  coroner  to 
analyze  the  material  for  mineral  and  vegetable  poisons. 
He  made  analyses  of  the  stomach  and  part  of  its  contents, 
and  a  portion  of  the  liver.  His  results  were  wholly  nega- 
tive. 

"  Mr.  F.  G.  Novy  tested  a  cold-water  extract  of  the  finely 
divided  intestine  for  ptomaines.  The  fluid,  which  was  acid 
in  reaction,  was  filtered,  then  neutralized  with  sodium 
bicarbonate,  and  shaken  with  ether.  The  ether,  after  sepa- 
ration, was  removed,  and  allowed  to  evaporate  spontaneously. 
The  residue  was  dissolved  in  water,  and  extracted  again  with 
ether.  This  ether  residue  gave  the  chemical  reactions  for 
tyrotoxicon,  and  a  portion  of  it  was  administered  to  a  kitten 
about  two  months  old.  Within  half  an  hour  after  the  ad- 
ministration the  kitten  began  to  retch,  and  soon  it  vomited. 
Within  the  next  three  hours  it  was  noticed  to  vomit  as 
many  as  five  times.  The  breathing  became  rapid  and 
labored.  The  animal  sat  with  its  head  down,  and  seemed 
greatly  prostrated.  The  pupils  were  examined,  but  could 
not  be  said  to  be  dilated.  There  was  no  purging.  The 
retching  and  heavy  breathing,  with  evidences  of  prostra- 
tion, continued  more  or  less  marked  for  two  days,  after 
which  the  animal  slowly  improved. 

"A  quantity  of  fresh  milk  was  divided  into  five  portions 
of  one  quart  each,  placed  in  quart  bottlas  "which  had  been 
thoroughly  cleansed,  and  treated  in  the  following  manner : 


POISONOUS    MILK.  79 

"  No.  1  consisted  of  the  milk  only,  and  was  employed  as 
a  control  test. 

"No.  2  was  mixed  with  a  drachm  of  vomited  matter. 

"No.  3  was  treated  with  a  portion  of  the  contents  of  the 
stomach . 

"No.  4  was  treated  with  an  a(|ueous  extract  of  the  intes- 
tine. 

"No.  5  was  treated  with  a  small  portion  of  the  soil  which 
had  been  taken  from  the  floor  of  the  buttery,  stirred  up 
with  water. 

"  These  bottles  were  placed  in  an  air-bath,  and  kept  at  a 
temperature  of  from  25°  to  30°  C.  for  twenty-four  hours. 
Then  each  was  tested  for  ptomaines.  No.  1  yielded  no 
tvrotoxicon,  while  all  of  the  others  contained  this  poison. 
The  tests  were  both  chemical  and  physiological.  All  of  the 
samples  yielded  a  non-poisonous  base  when  treated  according 
to  Brieger's  method,  and  the  same  substance  was  obtained 
from  perfectly  fresh  milk.  It  is  most  probably  formed  by 
the  action  of  the  heat  and  reagents  employed  in  this  method. 
This  base  was  obtained  in  crystalline  form,  and  several  por- 
tions of  it  were  administered  to  kittens  M'ithout  any  eifect. 
The  further  study  of  this  body  will  be  of  interest  to  toxi- 
cologists,  because  it  gives  many  of  the  general  alkaloidal 
reactions.  At  first  we  supposed  it  to  be  Brieger's  neuridine, 
and  this  supposition  may  still  be  correct,  but,  as  we  obtained 
it,  it  gave  some  reactions  which  are  not  given  by  neuridine, 
Further  investigations  will  be  made  on  this  point. 

"Tyrotoxicou  was  obtained  from  the  filtered  milk  by  two 
methods  :  (1)  The  one  which  we  have  previously  used,  and 
Avhich  consists  in  neutralizing  the  filtered  milk  with  sodium 
bicarbonate,  and  extracting  with  ether.  That  portion  of 
the  poison  employed  in  the  physiological  tests  was  obtained 
in  this  way,  and  in  order  to  be  sure  that  no  poison  came 


80  PTOMAINES. 

from  the  ether,  the  extract  frora  tlie  milk  to  which  nothing 
had  been  added  was  given  to  a  kitten,  and  was  found  to 
produce  no  eiFect.  (2)  The  fikrate  from  the  milk  was 
heated  to  70°  C.  (158°  F.)  (tyrotoxicou  decomposes  at  91° 
C.  (1 95.8°  F.))  for  some  minutes,  aud  filtered.  This  filtrate, 
which  was  perfectly  clear,  was  treated  with  a  small  quan- 
tity of  nitric  acid  in  order  to  convert  the  tyrotoxicou  into  a 
nitrate,  then  pure  potassium  hydrate  in  tlie  solid  form  was 
added  until  the  solution  was  strongly  alkaline.  This  solution 
was  concentrated  so  far  as  it  could  be,  on  the  water-bath.  (The 
potassium  compound  of  tyrotoxicou  is  not  decomposed  below 
130°  C.  (234°  F.).)  The  dark  brown  residue,  after  cooling, 
was  examined  with  the  microscope  and  found  to  contain  the 
crystalline  plates  of  tyrotoxicon-potassium  hydrate,  along 
with  the  prisms  of  potassium  nitrate.  The  former  was 
separated  from  the  latter  by  extraction  with  absolute  alcohol 
aud  filtration.  The  alcohol  was  evaporated  to  dryness  on 
the  water-bath,  and  the  residue  again  extracted  with  abso- 
lute alcohol.  From  this  alcoholic  solution  tyrotoxicou  was 
precipitated  with  ether.  The  precipitate  was  decomposed 
by  adding  acetic  acid  and  heating,  the  tyrotoxicou  being 
broken  up  into  nitrogen  and  phenol.  The  phenol  was 
recognized  by  precipitatiou  with  bromine  water,  aud  by 
other  well-known  tests. 

"On  October  8th,  the  coroner's  inquest,  which  had  been 
adjourned  after  the  post-mortem  in  order  to  await  the  re- 
sults of  the  analysis,  was  resumed,  aud  after  hearing  the 
testimony  in  accordance  with  the  above  stated  facts,  the 
jury  returned  a  verdict  of  death  from  poisoning  with  tyro- 
toxicou." 

Poisonous  Ice-cream.  —  In  1886,  Yaughan  and 
NovY    obtained    tyrotoxicou   from   a   cream   which  had 


POISONOUS    ICE-CREAM.  81 

seriously  aifected  many  persons  at  Lawton,  Michigan. 
Vanilla  had  been  used  for  flavoring,  and  it  was  supposed 
that  the  ill-eifects  were  due  to  the  flavoring.  This  belief 
was  strengtiiened  by  the  fact  that  a  portion  of  the  custard 
was  flavored  with  lemon,  and  the  lemon  cream  did  not 
aflect  any  one  unj)leasantly.  Fortunately,  some  of  the 
vanilla  extract  remained  in  the  bottle  from  which  the 
flavoring  for  the  ice-cream  had  been  taken,  and  this  was 
forwarded  to  the  chemists.  Each  of  the  experimenters 
took  at  first  thirty  drops  of  the  vanilla  extract,  and  no  ill- 
effects  following  this,  one  of  them  took  two  teaspoonfuls 
more,  with  no  results.  This  proved  the  non-poisonous 
nature  of  the  vanilla  more  satisfactorily  than  could  have 
been  done  by  a  chemical  analysis. 

Later,  it  was  fom^d  that  that  portion  of  tlie  custard 
which  had  been  flavored  with  lemon  was  frozen  immedi- 
ately ;  while  that  portion  which  was  flavored  with  vanilla 
and  which  proved  to  be  poisonous,  was  allowed  to  stand 
for  some  hours  in  a  building,  which  is  described  as  follows 
by  a  resident  of  the  village  : 

"  The  cream  was  frozen  in  the  back  end  of  an  old 
wooden  building  on  Main  Street.  It  is  surrounded  by 
shade,  has  no  underpinning,  and  the  sills  have  settled  into 
the  ground.  There  are  no  eve-troughs,  and  all  the  water 
falling  from  the  roof  runs  under  the  building,  the  streets 
on  two  sides  iiaviug  been  raised  since  the  construction  of 
the  house.  The  building  had  been  unoccupied  for  a 
number  of  months,  consequently  had  had  no  ventilation, 
and  what  is  worse,  the  back  end  (where  the  cream  was 
frozen)  was  last  used  as  a  meat  market.  The  cream  which 
was  affected  was  that  portion  last  frozen ;  consequently  it 
stood  in  an  atmosphere  like  that  of  a  privy  vault  for  up- 
ward of  an  hour  and  a  half  or  two  hours  before  being  frozen." 


82  PTOMAINES. 

The  symptoms  observed  in  these  cases  are  given  by  Dr. 
MoFiTT  as  follows  : 

"About  two  hours  after  eating  the  cream  every  one  was 
taken  with  severe  vomiting,  and  after  from  one  to  six  hours 
later  with  purging.  The  vomit  was  of  a  soapy  character, 
and  the  stools  watery  and  frothy.  There  was  some  griping 
of  the  stomach  and  abdomen,  with  severe  occipital  head- 
ache, excruciating  backache,  and  bone  pains  all  over,  espe- 
cially marked  in  the  extremities.  The  vomiting  lasted 
from  two  to  three  hours,  then  gradually  subsided,  and 
everybody  felt  stretchy,  and  yawned  in  spite  of  all  resist- 
ance. The  throats  of  all  were  oedematous.  One  or  two 
were  stupefied  ;  others  were  cold  and  experienced  some 
muscular  spasms.  A  numb  feeling,  with  dizziness  and 
momentary  loss  of  consciousness,  was  complained  of  by 
some.  Temperature  was  normal,  and  pulse  from  90  to  120. 
Tongue  dry  and  chapped.  All  were  thirsty  after  the 
vomiting  subsided,  and  called  for  cold  water,  which  was 
allowed  in  small  quantities,  with  no  bad  results.  After 
getting  out  no  one  of  the  victims  was  able  to  be  in  the  hot 
sun  for  several  days,  and  even  yet  (about  ten  days  after  the 
poisoning)  the  heat  aflPects  myself.  I  attended  twelve 
persons,  besides  being  sick  myself,  and  all  were  affected 
in  pretty  much  the  same  way.  Several  complain  yet  of 
inability  to  retain  food  on  the  stomach  -without  distressing 
them.  The  man  who  made  the  cream  took  a  teaspoonful 
of  it,  and  he  vomited  the  same  as  those  who  took  a  whole 
dish,  but  not  so  often  or  for  so  long  a  time.  All  are 
affected  with  an  irresistible  desire  to  sleep,  which  can 
scarcely  be  overcome.  Even  yet,  some  of  us  feel  that 
drowsy  condition,  with  occasional  occipital  headache." 

The  tyrotoxicou  obtained  from  this  cream  was  adminis- 
tered to  a  kitten  about  two  months   old.      Within   ten 


POISONOUS    IC^E-CREAM.  83 

minutes  the  cat  begau  to  retch  and  soon  it  vomited.  This 
retching-  and  vomiting  continued  for  two  hours,  during 
which  the  animal  was  under  observation,  and  the  next 
morning  it  was  observed  that  the  animal  had  passed  several 
watery  stools.  After  this,  although  the  animal  could  walk 
about  the  room,  it  was  unable  to  retain  any  food.  Several 
times  it  was  observed  to  lap  a  little  milk,  but  on  doing  so 
it  would  immediately  begin  to  retch  and  vomit.  Even  cold 
water  produced  this  eifect.  This  condition  continuing, 
after  three  days  the  animal  was  placed  under  ether  and  its 
abdominal  organs  examined.  Marked  inflammation  of  the 
stomach  was  supposed  to  be  indicated  by  the  symptoms, 
but  the  examination  revealed  the  stomach  and  small  intes- 
tine filled  with  a  frothy,  serous  fluid,  such  as  had  formed 
a  portion  of  the  vomited  matter,  and  the  mucous  membrane 
very  white  and  soft.  There  was  not  the  slightest  redness 
anywhere.  The  liver  and  other  abdominal  organs  seemed 
normal. 

A  bit  of  the  solid  portion  of  this  cream  was  added  to 
some  normal  milk,  which,  by  the  addition  of  eggs  and 
sugar,  was  made  into  a  custard.  The  custard  was  allowed 
to  stand  for  three  hours  in  a  warm  room,  after  which  it 
was  kept  in  an  it-e-box  until  submitted  to  chemical  analysis. 
In  this  tyrotoxicon  was  also  found. 

Tyrotoxicon  has  since  been  found  in  some  chocolate 
cream  which  poisoned  persons  at  Geneva,  N.  Y.,  and  in 
lemon  cream  from  Amboy,  Ohio. 

ScHEARER  reports  the  finding  of  tyrotoxicon  in  both 
vanilla  and  lemon  ice-cream  which  made  many  sick  at 
Nugent,  Iowa. 

Allaben  reports  poisoning  with  lemon  cream,  and  makes 
the  following  interesting  statements  concernintr  it : 

"  I  would  first  say  July  4,  5,  and  6  were  very  warm. 


84  PTOMAINES. 

Monday  evening,  July  5,  the  custards  were  cooked,  made 
from  Monday  morning's  cream  and  Monday  night's  milk, 
boiled  in  a  tin  pan  that  had  the  bright  tin  worn  off.  It 
was  noticed  that  one  pan  of  cream  was  not  sweet,  but 
thinking  it  would  make  no  difference,  it  was  used ;  the 
freezers  were  thoroughly  cleaned  and  scalded,  and  the 
custards  put  in  the  same  evening  while  hot ;  the  cream  was 
frozen  Tuesday  afternoon,  having  stood  in  the  freezers 
since  the  night  before,  when  the  weather  was  very  warm." 

No  analysis  of  this  cream  was  made,  but  the  symptoms 
agree  with  those  of  tyrotoxicon  poisoning. 

Welford  observed  several  cases  of  poisoning  from 
custard  flavored  with  lemon.  These  custards  were  tested 
for  mineral  poisons,  with  negative  results. 

Morrow  has  put  forth  the  claim  that  ice-cream  poisoning 
is  solely  due  to  vanilla,  which  is,  according  to  his  statement, 
used  instead  of  vanilla  extract,  but  the  facts  stated  above 
concerning  poisoning  with  creams  in  which  other  flavors 
had  been  used  contradict  this  claim.  Moreover,  Gibson 
has  shown  the  utter  absurdity  of  the  claim,  inasmuch  as 
he  calculates  from  the  amount  of  flavoring  ordinarily 
used  in  ice-cream,  that  in  order  to  produce  the  toxic  symp- 
toms observed,  the  flavoring  must  be  ten  times  as  poisonous 
as  pure  strychnia. 

Bartley  suggests  that  poisonous  cream  sometimes 
results  from  the  use  in  its  manufacture  of  poor  or  putrid 
gelatine.  This  is  highly  probable,  and  with  the  gelatine 
the  germs  of  putrefaction  may  be  added  to  the  milk. 

Poisonous  Meal  and  Bread. — Reference  has  already 
been  made  to  the  fact  that  the  peasants  in  certain  parts  of 
Italy  are  frequently  poisoned  by  eating  mouldy  corn-meal. 
As  has  also  been  stated,  Lombroso  and  others  have  ob- 


POISONOUS    MEAL    AND    BREAD.  85 

tained  from  this  meal  ptomaines,  some  of  M'hich  give  the 
same  color  reaction  as  strychnine.  In  1886,  Ladd  suc- 
ceeded in  isolating  from  "  heated  "  corn-meal  a  ptomaine 
which  forms  in  urea-like  crystals.  The  quantity  was  not 
sufficient  for  an  ultimate  analysis,  and  the  physiological 
action  has  not  been  studied.  Poisoning  from  decomposed 
and  mouklv  hrcad  is  not  unknown. 


CHAPTEK    III. 

THE  RELATION  OF  PTOMAINES  TO  DISEASE. 

That  specific  microorganisms  are  concerned  in  the  causa- 
tion of  certain  diseases  cannot  now  be  questioned.  The 
evidence  on  this  point,  for  a  few  diseases  at  least,  amounts 
to  a  positive  demonstration.  The  rules  given  by  Koch 
for  determining  whether  or  not  a  given  bacterium  is  the 
cause  for  a  certain  disease  do  not  admit  of  any  question 
when  they  are  fully  complied  with.  While  it  is  not  our 
purpose  to  treat  of  questions  of  bacteriology,  it  may  be  well 
in  order  to  discuss  intelligently  the  relation  of  ptomaines 
to  disease,  and  in  order  to  have  the  chain  of  evidence  un- 
broken, to  give  briefly  these  rules.  In  a  condensed  form 
they  may  be  stated  as  follows  : 

(1)  The  special  bacterium  must  be  present  in  all  cases  of 
that  disease. 

The  importance  of  this  rule  is  self-evident.  If  one  case 
of  the  disease  could  be  found  in  which  the  microorganism 
did  not  exist,  then  its  supposed  causal  relation  to  that  dis- 
ease must  be  false.  However,  the  invariable  presence  of 
any  germ  in  a  certain  disease  does  not  prove  that  the  former 
is  the  cause  of  the  latter.  Indeed,  so  long  as  the  investiga- 
tion goes  no  further  than  this,  we  are  justified  in  saying 
that  the  microorganism  may  be  an  accompaniment  or  a 
consequence  of  the  disease.  Therefore,  additional  evidence 
is  wanting  and  is  furnished  by  complying  with  the  other 
rules  of  Koch. 

(2)  The  special  microorganism  must  be  freed  from  other 


RELATION    OF    PTOMAINES    TO    DISEASE.       87 

organisms  and  from  all  matter  found  witli  it  in  the  diseased 
animal. 

This  is  done  by  carryino;  the  organism  throngh  succes- 
sive cultures. 

(3)  The  special  germ,  thus  freed  from  all  foreign  matter, 
must,  when  properly  introduced,  produce  the  disease  in 
healthy  animals. 

(4)  The  micro(")rganism  must  be  found  properly  distrib- 
uted in  the  animal  in  which  the  disease  has  been  induced. 

All  of  these  conditions  must  be  fulfilled  before  it  can  be 
satisfactorily  demonstrated  that  a  specific  organism  is  the 
cause  of  a  given  disease,  and  in  certain  diseases  this  com- 
plete demonstration  has  been  made. 

Recognizing  the  fact  that  germs  do  bear  a  causal  relation 
to  some  diseases,  the  question  arises.  How  do  these  organ- 
isms produce  disease?  In  what  way  does  the  bacillus  an- 
thracis,  for  instance,  induce  the  symptoms  of  the  disease 
and  death  ?  Many  answers  to  this  question  have  been 
offered.  Some  of  the  most  important  of  these  are  as 
follows : 

(1)  It  was  first  suggested  by  Bollinger  that  apoplecti- 
form anthrax  was  due  to  deoxidation  of  the  blood  by  the 
bacilli.  These  germs  are  aerobic,  and  were  supposed  to 
deprive  the  red  blood-corpuscles  of  their  oxygen.  This 
theory  was  suggested  most  probably  by  the  resemblance  of 
the  symptoms  to  those  of  carbonic  acid  poisoning.  The 
most  prominent  of  these  symptoms  are  dyspnoea,  cyanosis, 
convulsions,  dilated  pupils,  subnormal  temperature,  and,  in 
general,  the  phenomena  of  asi)hyxia.  Moreover,  post- 
mortem examination  reveals  conditions  similar  to  those 
observed  after  death  by  deprivation  of  oxygen.  The  veins 
are  distended,  the  blood  is  dark  and  thick,  the  parenchy- 
matous  organs   are   cyanotic,  and   the  lungs   hyperjemic. 


08  PTOMAINES. 

Bollinger  compared  this  form  of  anthrax  to  poisoning 
with  hydrocyanic  acid,  which  was  then  believed  to  produce 
fatal  results  by  robbing  the  blood  of  its  oxygen. 

This  theory  was  supported  by  the  observations  of  SzpiL- 
MAXN,  who  found  that  while  the  putrefactive  bacteria  were 
destroyed  by  ozone,  the  bacillus  anthracis  thrived  and  mul- 
tiplied in  this  gas. 

This  theory  presupjjosed  a  large  number  of  bacilli  in  the 
blood,  and  this  accorded  with  the  estimate  of  Davaine, 
which  placed  the  number  at  from  .eight  to  ten  million  in  a 
single  drop.  But  more  extended  and  careful  observation 
showed  that  the  blood  of  animals  dead  from  anthrax  is 
often  very  poor  in  bacilli.  Viechow  reported  cases  of 
this  kind.  Bollinger  himself  found  the  bacilli  often 
only  in  certain  positions  and  not  abundant  in  the  blood. 
Then  Siedamgrotzky  counted  the  organisms  in  the  blood 
in  various  cases  and  found  not  only  that  the  estimate  made 
by  Davaine  was  too  large,  but  that  in  many  instances  the 
number  present  in  the  blood  was  small.  Joffroy  found 
in  some  of  his  inoculation  experiments  that  the  animals 
died  before  any  bacilli  appeared  iu  the  blood.  These  and 
other  investigations  of  similar  character  began  to  cau.se 
workers  in  this  field  of  research  to  doubt  the  truth  of  the 
theory  of  Bollinger.  These  doubts  were  soon  converted 
into  po,sitive  evidence  again.st  the  theory.  Pasteur,  in 
support  of  the  theory,  reported  that  birds  were  not  suscept- 
ible to  anthrax,  and  he  accounted  for  this  by  supposing 
that  the  blood  corpuscles  in  birds  do  not  part  with  their 
oxygen  readily.  However,  it  was  shown  by  Oemler  and 
Feser  that  the  learned  Frenchman  had  generalized  from 
limited  data,  and  tliat  many  birds  are  especially  susceptible 
to  the  disea.se.  Oemler  found  that  the  blood  even  when 
rich  iq  bacilli  .still  possessed  the  bright  red  color  of  oxy- 


RELATION    OK    PTOMAINES    TO    DISEASE.       89 

hseraojilobin.  Toepper  and  Roloff  reported  cases  of 
apoplectiform  authrax  in  which  there  was  no  difficulty  in 
respiration.  Toussaint  caused  animals  which  had  been 
inoculated  with  the  anthrax  bacillus  to  breathe  air  con- 
tainino;  a  laro-e  volume  of  oxv";en,  and  found  that  this  did 
not  modify  the  symptoms  or  retard  death.  Finally, 
Nencki  determined  the  amount  of  physiological  oxidation 
going  on  in  the  bodies  of  animals  sick  with  anthrax  by 
estimating  the  amount  of  phenol  excreted  after  the  adminis- 
tration of  one  gram  of  benzol,  and  found  that  the  oxida- 
tion of  the  benzol  was  not  diminished  by  the  disease.  Thus, 
the  theory  that  germs  destroy  life  by  depriving  the  blood 
of  its  oxygen  has  been  found  not  to  be  true  for  authrax, 
and  if  not  true  for  anthrax,  certainly  it  cannot  be  for  any 
other  known  disease.  The  bacillus  anthracis  is,  as  has  been 
stated,  aerobic,  while  most  of  the  pathogenic  bacteria  are 
anaerobic — that  is,  they  live  in  the  absence  of  oxygen.  This 
element  is  not  necessary  to  their  existence,  and,  indeed, 
when  present  in  large  amount,  it  is  fatal  to  their  existence. 
Moreover,  in  many  diseases,  the  bacteria  are  not  found  in 
the  blood  at  all.  Lastly,  the  symptoms  of  these  diseases 
are  not  those  of  asphyxia.  These  facts  have  caused  all 
bacteriologists  to  acknowledge  that  this  theory  is  not  the 
right  one. 

(2)  If  a  properly  stained  section  of  a  kidney  taken  from 
a  guiuea-pig,  which  has  been  inoculated  with  the  bacillus 
anthracis,  be  examined  under  a  microscope,  the  bacilli  will 
be  found  to  be  present  in  such  large  numbers  that  they  form 
emboli,  which  not  only  close,  but  actually  distend  the 
capillaries  and  larger  bloodvessels,  and  interfere  with  the 
normal  functions  of  the  organ.  A  similar  condition  is 
sometimes  found  on  microscopical  examination  of  the  liver, 
spleen,  and  lungs.     From  these  appearances,  it  was  inferred 

8* 


90  PTOMAINES. 

by  Bollinger  that  the  bacilli  produce  the  diseased  condi- 
tion simply  t^'-  accumulating  in  large  numbers  in  these 
important  organs,  and  mechanically  interrupting  their 
functions.  Tiiis  is  knov.n  as  the  mechanical  interference 
theory. 

Klees  and  Toussaint  were  formerly  ardent  advocates 
of  tljis  theory  in  its  application  to  anthrax,  and  the  latter 
thought  that  the  symptoms  and  death  are  due  to  stoppage 
of  the  pulmonary  circulation  by  means  of  emboli.  How- 
ever, HoFFA  studied  this  point  by  making  numerous  post- 
mortem examinations,  and  was  unable  to  confirm  it.  A 
like  result  followed  the  work  of  Viechow,  Colin,  and 
SiEDAMGEOTZKY,  and  the  mechanical  interference  theory 
has  Ijeen  abandoned. 

In  the  majority  of  germ  diseases  this  theory  never  had 
any  support.  There  is  not  found  any  great  accumulation 
of  bacteria  in  any  organ,  and  the  number  and  distribution 
of  the  germs  are  such  that  the  theory  of  mechanical  inter- 
ference cannot  be  held  at  all. 

(3)  Another  answer  given  to  the  fjuestion,  How  do  germs 
cause  disease  ?  is,  that  they  do  so  by  consuming  the 
proteids  of  the  body  and  thus  deprive  it  of  its  sustenance. 
The  proteids  are  known  to  be  necessary  for  the  building  up 
of  cells,  and  it  is  also  known  that  microorganisms  feed 
upon  proteids.  But  this  theory  is  untenable  for  several 
reasons.  In  the  first  place,  many  of  the  infectious  diseases 
destroy  life  so  cjiuickly  that  the  fatal  effect  cannot  be  sup- 
posed to  be  due  to  the  consumption  of  any  very  large 
amount  of  proteid.  In  the  second  place,  the  distribution 
of  the  microorganisms  is  such  in  many  diseases  that  they 
do  not  come  in  contact  with  any  large  proportion  of  the 
proteids  of  the  body.  In  the  third  place,  the  symptoms  of 
the  majority  of  these  diseases  are  not  those  which  would 


RELATION    OF    PTOMAINES    TO    DISEASE.       91 

be  produced  by  witli(h'awin<2;  from  the  various  orj^aiis  their 
food.     The  symptoms  are  not  tliose  of  general  starvation. 

(4)  Still  another  theory,  which  has  been  oifered,  is  that 
the  bacteria  destroy  the  blood  corpuscles,  or  lead  to  their 
rapid  disintegration.  But  in  many  of  the  infectious  dis- 
eases, as  has  been  stated,  the  microorganisms,  although 
very  abundant  in  some  organs,  are  not  present  in  the  blood 
at  all.  Moreover,  the  disintegration  of  the  blood  corpuscles 
is  not  confirmed  by  microscopical  examination. 

(5)  Seeing  the  vital  deficiencies  in  the  above  theories,  and 
being  impressed  by  the  results  obtained  by  the  chemical 
study  of  putrefaction,  bacteriologists  have  been  led  to  in- 
quire into  the  possibility  of  the  symptoms  of  the  infectious 
diseases  being  due  to  chemical  poisons.  In -investigating 
this  theory,  three  possibilities  suggest  themselves  : 

(a)  The  microorganisms  themselves  may  be  poisonous,  or 
the  poison  may  be  an  integral  part  of  them.  Neelsen,  at 
one  time  an  advocate  of  this  theory,  thus  accounted  for 
the  appearance  and  increase  in  violence  of  the  symptoms  as 
the  germs  increase  in  numbers.  In  order  for  the  conditions 
of  this  theory  to  be  fulfilled,  the  microorganisms  must  be 
present  in  the  blood  before  any  of  the  symptoms  appear. 
But  in  anthrax,  the  most  thoroughly  studied  of  all  the  in- 
fectious diseases,  and  the  one  to  which  all  these  theories 
have  been  applied,  the  bacilli  first  appear  in  the  blood,  as  a 
rule,  only  a  few  hours  l)efore  death,  and  long  after  the 
appearance  of  the  first  symptoms ;  while  in  many  other 
diseases  the  germs  are  never  found  in  the  blood.  More- 
over, as  HoFFA  has  shown,  if  this  theory  be  true,  the  in- 
jection of  a  large  quantity  of  anthrax  bacilli  directly  into 
the  blood  should  be  followed  immediately  by  symptoms  of 
the  disease,  and  death  should  be  speedy.  But  he  found,  on 
making  experiments  of  this  kind,  that  the  symptoms  did 


92  PTOMAINES. 

not  appear  until  from  twenty -four  to  seventy-two  hours. 
Finally,  Nencki,  by  chemical  analysis  of  the  substance  of 
anthrax  bacilli,  has  shown  that  in  some  respects  it  resem- 
bles vegetable  casein,  and  in  others,  animal  mucin.  This 
"  anthrax-protein  "  is  freely  soluble  in  alkalies,  is  insoluble 
in  water,  acetic  acid,  and  the  dilute  mineral  acids.  It 
contains  no  sulphur,  and  is  not  poisonous. 

(6)  The  micro5rganisms  may  be  intimately  associated 
with  or  may  produce  a  soluble,  chemical  ferment,  which, 
by  its  action  on  the  body,  produces  the  symptoms  of  the 
disease  and  death.  This  theory  formerly  had  a  number  of 
ardent  supporters,  among  whom  might  be  mentioned  the 
eminent  scientist,  de  Baey.  But  Pasteur  proved  the 
theory  false  when  he  filtered  anthrax  blood  through  earthen 
cylinders,  inoculated  animals  with  the  filtrate,  and  failed  to 
produce  any  effect,  Nencki  made  a  similar  demonstration 
when  he  inoculated  a  two  per  cent,  gelatine  preparation 
with  the  anthrax  bacillus,  which  liquefied  the  preparation, 
and  on  standing  the  bacilli  settled  to  the  bottom.  The 
supernatant  fluid,  which  was  clear,  alkaline  in  reaction,  and 
contained  dissolved  "■  anthrax-protein,"  was  filtered  and 
injected  into  animals  without  producing  any  effect. 

(c)  The  bacillus  may  produce  a  chemical  poison  by 
splitting  up  preexisting,  complex  compounds  in  the  body. 
This  theory  is  supported  by  analogy,  when  we  remember 
that  the  ordinary  putrefactive  germs  produce  such  chemical 
poisons,  as  has  been  demonstrated  by  the  work  of  Panum 
and  others.  These  poisons  are  ptomaines,  and  the  truth  of 
this  theory  may  now  be  said  to  amount  to  a  positive  de- 
monstration. We  now  expect  to  find  each  specific,  patho- 
genic microorganism  producing  its  own  characteristic 
poison  or  poisous.     The  evidence  on  this  point  we  will  give 


RELATION    OF    PTOMAINES    TO    DISEASE.        93 

further  on  in  a  brief  sketch  of  some  of  tiie  best  known 
infectious  diseases. 

Before  taking  up  the  individual  diseases,  we  will  give 
what  appears  to  us,  in  the  present  state  of  our  knowledge, 
a  correct  definition  of  an  infectious  disease. 

An  infectious  disease  arises  when  a  specific,  pathogenic 
microorganism,  having  gained  admittance  to  the  body,  and 
having  found  the  conditions  favorable,  grows  and  multi- 
plies, and  iu  so  doing  elaborates  a  chemical  poison  which 
induces  its  characteristic  effects. 

In  the  systemic  infectious  diseases,  such  as  anthrax, 
typhoid  fever,  and  cholera,  this  poison  is  undoubtedly  taken 
into  the  general  circulation,  and  affects  the  central  nervous 
system.  In  the  local  infectious  diseases,  such  as  gonorrhoea, 
and  infectious  ophthalmia,  the  principal  action  of  the  poison 
seems  to  be  confined  to  the  place  of  its  formation.  Though 
even  in  these,  when  of  a  specially  virulent  type,  the  effects 
may  extend  to  the  general  health.  It  may  be  that  in  some 
diseases  the  chemical  poison  has  both  a  local  and  a  systemic 
effect.  Thus,  it  is  by  no  means  certain  that  the  ulceration 
of  typhoid  fever  is  due  directly  to  the  bacillus.  On  the 
other  hand,  it  is  altogether  probable  that  the  anatomical 
changes  in  the  intestine  result  from  the  irritating  effects  of 
the  ptomaine  at  the  place  of  its  formation. 

In  a  recent  article,  I^eelsen  has  given  the  following 
classification  of  germ  diseases  : 

(1)  General  acute  mycoses.  In  this  class  of  diseases,  the 
germ  grows  exclusively  in  the  bloodvessels,  from  which  it 
is  not  able  to  escape.  However,  at  the  point  of  inoculation 
it  may  produce  lesions  in  the  form  of  inflammatory  oedema 
or  hemorrhagic  infiltration.  As  types  of  this  class,  may  be 
mentioned  authrax,  and  mouse-septicoemia. 

The  deleterious  effects  do  not  result  from  the  consump- 


94:  pto:m:aixes. 

tion  of  any  importaut  constituent  of  the  body  by  the 
germs,  but  from  the  formation  of  poisons,  ptomaines.  The 
injury  inflicted  by  the  disease,  or  the  danger  to  hfe,  will  be 
in  proportion  to  the  multiplication  of  the  bacteria,  and  the 
consequent  amount  of  the  poison  produced. 

In  some  of  these  diseases  a  very  small  number  of 
bacteria  seem  to  be  able  to  produce  a  poison  of  great 
intensity.  This  is  true  of  septicaemia  in  man  and  in  the 
rabbit. 

To  this  class  beloug  the  intermittent  acute  mycoses,  in 
which  there  is  only  a  periodic  accumulation  of  the  bacteria 
in  the  blood.    Recurrent  fever  is  given  as  an  illustration. 

(2)  Diseases  icith  loeal  development  of  bacteria.  In  these 
diseases  the  bacteria  multiply  only  in  the  neighborhood  of 
the  point  of  inoculation.  Thase  diseases  are  subdivided 
into  four  classes :  (a)  The  bacteria  developing  locally  pro- 
duce a  ptomaine,  which  is  absorbed  and  produces  a  general 
intoxication,  which  is  the  most  prominent  symptom  of  the 
disease.  Cholera,  tetanus,  and  putrid  intoxication  are 
examples.  (6)  The  general  intoxication  is  present,  but  is 
overshadowed  by  the  local  inflammatory  changes.  Malig- 
nant cedema,  erysipelas,  and  pneumonia  are  representatives 
of  this  class,  (c)  The  local  effects  lead  to  necrotic  changes, 
as  in  hospital  gangrene  and  gangrene  foudroyante.  {d) 
The  local  development  of  the  bacteria  leads  to  suppuration. 

(3)  Mycoses  of  the  blood  ivith  secondary  local  affections. 
The  bacteria  grow  and  multiply  in  the  blood,  but  the  most 
prominent  effects  of  the  poison  are  manifest  in  local  lesions, 
which  may  be  simply  inflammatory,  suppurative,  or  necrotic. 
As  examples  of  such  mycosas  with  mtiltiple  secondary 
inflammatory  lesions,  we  have,  in  man,  measles,  German 
measles,  scarlet  fever,  acute  articular  rheumatism,  and  beri- 
beri ;  in  the  lower  animals,  chicken  cholera. 


ANTHRAX.  95 

As  mycoses  of  the  blood  with  secondary  suppuration  and 
necrosis,  we  may  mention  variola,  diphtheria,  and  osteo- 
malacia. 

(4)  Mycoses  with  tissue  'proliferation  or  infective  ulcers. 
The  new  formations  show  a  tendency  to  degenerative 
changes,  suppuration,  and  necrosis.  Such  are  typhoid 
fever,  glanders,  tuberculosis,  leprosy,  and  syphilis. 

Anthrax. — The  definition  of  an  infectious  disease,  as 
we  have  giv^eu  it,  is  well  illustrated  by  the  facts  which  have 
been  learned  concerning  the  causation  of  anthrax,  which, 
probably,  has  been  more  thoroughly  studied  than  any  other 
infectious  disease.  Kausch  taught  that  anthrax  had  its 
origin  in  paralysis  of  the  nerves  of  respiration.  Delafond 
thought  that  the  cause  of  the  disease  was  to  be  found  in  the 
influence  of  the  chemical  composition  of  the  soil  affecting 
the  food  of  animals,  and  leading  to  abnormal  nutrition. 
The  investigations  of  Gerlach,  in  1845,  demonstrated  the 
contagious  nature  of  the  disease,  which  was  emphasized  by 
Heusinger  in  1850,  and  accepted  by  Virchow  in  1855. 
However,  in  1849,  Pollender  found  numerous,  rod-like 
microorganisms  in  the  blood  of  animals  with  the  disease. 
This  observation  was  confirmed  by  Brauell,  who  pro- 
duced the  disease  in  healthy  animals,  by  inoculation  with 
matter  taken  from  a  pustule  on  a  sick  horse.  Attempts 
were  made  to  ridicule  the  idea  that  these  germs  might  be 
the  cause  of  the  disease,  and  it  was  said  that  the  bodies 
seen  w'ere  only  fine  pieces  of  fibrin,  or  blood-crystals.  But, 
in  1863,  Davaine  showed  that  these  little  bodies  must 
have  some  causal  relation  to  the  disease,  inasmuch  as  his 
experiments  proved  that  inoculation  of  healthy  animals 
with  the  blood  of  animals  sick  with  anthrax  produced  the 
disease  only  when  the  blood  contained  these  organisms.   He 


96  PTOMAINES. 

also  demonstrated  l^eyond  auy  question,  that  these  bodies 
were  bacteria.  The  conclusions  of  this  investigator  were 
earnestly  combated  by  many.  But  Pasteur,  Koch, 
Bollinger,  de  Bary,  and  others,  studied  the  morphology 
and  life-history  of  these  organisms,  and  then  came  the  bril- 
liant results  of  Pasteur  and  Koch  in  securing  protection 
against  the  disease  by  the  vaccination  of  healthy  animals 
with  the  modified  germ.  Now,  the  bacillus  anthracis  is 
known  in  every  bacteriological  laboratory,  and  by  inocula- 
tion with  it  the  disease  is  communicated  at  will  to  animals. 
But,  here  the  question  arose.  How  do  these  bacilli  produce 
anthrax  ?  and,  in  answer  to  this  question,  the  various  theo- 
ries which  we  have  mentioned  were  proposed.  Recently, 
HoFFA  has  given  us  the  true  answer  by  obtaining  from 
pure  cultures  of  the  bacillus  anthracis  a  ptomaine  which, 
when  injected  under  the  skin  of  animals,  produces  the 
symptoms  of  the  disease  followed  by  death.  The  anthrax 
ptomaine  causes  at  first  increased  respiration  and  action  of 
the  heart,  then  the  respirations  become  deep,  slow,  and 
irregular.  The  temperature  falls  below  the  normal.  The 
pupils  are  dilated,  and  a  bloody  diarrhoea  sets  in.  On  sec- 
tion, the  heart  is  found  contracted,  the  blood  dark,  and 
ecchymoses  are  observed  on  the  pericardium  and  peri- 
toneum. 

Cholera. — Although  the  ptomaine  of  cholera  has  not 
been  isolated,  there  are  reasons  for  believing  that  the  comma 
bacillus  of  Koch  is  one  of  the  most  active  chemically  of 
all  known  pathogenic  microorganisms.  In  the  first  place. 
Bitter  has  shown  that  this  germ  produces  in  meat-peptone 
cultures  a  peptonizing  ferment,  which  remains  active  after 
the  organism  has  been  destroyed.  It  was  shown  that  this 
ferment,  like  similar  chemical  ferments,  would  convert  an 


CHOLERA.  97 

indefinite  amonnt  of  gelatine  or  coagnlated  albnmen  into 
peptone.  It  was  also  demonstrated  that  this  ferment  was 
more  active  in  alkaline  than  in  acid  solutions,  thus  proving 
that  it  resembles  pancreatin  more  than  pepsin.  This 
resemblance  to  pancreatin  was  further  demonstrated  by 
the  fact  that  certain  chemicals,  such  as  sodium  carbonate 
and  sodium  salicylate,  increased  its  activity. 

That  a  diastasic  ferment  is  also  produced  by  the  growth  of 
this  bacillus  was  indicated  by  the  development  of  an  acid 
in  nutrient  solutions  containing  starch  paste.  However,  all 
attempts  to  isolate  the  diastasic  ferment  were  unsuccessful. 
A  temperature  of  60°  destroys  or  greatly  decreases  the 
activity  of  ptyalin,  and  this  seems  to  be  also  true  of  the 
diastasic  ferment  proiluced  by  the  comma  bacillus.  But  the 
formation  of  an  acid  from  the  starch  presupposes  that  the 
starch  is  first  converted  into  a  soluble  form. 

[It  is  proper  to  mention  here  that  Sternberg,  indepen- 
dently of  the  experiments  of  Bittphi,  has  shown  that  a 
number  of  microorganisms  are  capable  of  producing  a  pep- 
tonizing ferment,  which  remains  active  after  destroying  the 
germs  by  raising  the  temperature  of  the  culture  to  80°. 
Sternberg  experimented  with  bacillus  prodigiosus,  b. 
indicus,  b.  pyocyanus  and  Finkler-Prior's  spirillum.  It 
is  probable  that  all  germs  which  liquefy  gelatine  do  so  by 
the  production  of  this  ferment.] 

In  order  to  investigate  the  digestive  action  of  bacteria, 
RiETSCH  precipitated  peptone  cultures  of  the  cholera  bacil- 
lus, typhoid  bacillus,  bacillus  of  consumption,  and  staphylo- 
coccus aureus  with  alcohol,  collected,  washed,  dried,  and 
weighed  the  precipitates  and  tested  their  action  upon  coagu- 
lated fibrin.  The  powders  thus  obtained  from  cultures  of 
the  typhoid  and  consumption  bacilli  had  no  digestive  action 
in  either  neutral  or  alkaline  fluids.    On  the  other  hand,  the 


98  PTOMAINES. 

precipitates  obtained  from  the  cultures  of  the  cholera  bacil- 
lus and  the  staphylococcus  aureus,  the  latter  less  energeti- 
cally than  the  former,  dissolved  the  fibrin  and  the  solutions 
gave  reactions  for  peptones. 

RiETSCH  believes  that  the  destructive  changes  observed 
in  the  intestines  in  cholera  are  due  to  the  action  of  this 
peptonizing  ferment. 

Cantani  injected  sterilized  cultures  of  the  comma  bacillus 
into  the  peritoneal  cavities  of  small  dogs  and  observed  after 
from  one-quarter  to  one-half  hour  the  following  symptoms : 
great  weakness,  tremor  of  the  muscles,  drooping  of  the  head, 
prostration,  convulsive  contractions  of  the  posterior  extremi- 
ties, repeated  vomiting,  and  cold  head  and  extremities. 
After  two  hours  these  symptoms  began  to  abate,  and  after 
twenty-four  hours  the  recovery  seemed  complete.  Control 
experiments  with  the  same  amounts  of  uninfected  beef-tea 
were  made  with  negative  results.  These  cultures  'were  three 
days  old  when  sterilized.  Older  cultures  seemed  less  poison- 
ous, and  a  high  or  prolonged  heat  in  sterilization  decreased 
the  toxicity  of  the  fluid.  From  these  facts  Cantani  con- 
cludes that  the  poisonous  principle  is  volatile.  The  cultures 
in  bouillon  containing  peptone  were  more  poisonous  than 
those  in  simple  bouillon. 

Klebs  has  attempted  to  answer  experimentally  the  ques- 
tion. In  what  way  does  the  cholera  germ  prove  harmful  ? 
Cultures  of  the  bacillus  in  fish  preparations  w'ere  acidified, 
filtered,  the  filtrate  evaporated  on  the  water-bath,  the  residue 
taken  up  with  alcohol  and  precipitated  with  platinum  chlo- 
ride. The  platinum  was  removed  with  hydrogen  sulphide, 
and  the  crystalline  residue  obtained  on  evaporation  was  dis- 
solved in  water  and  injected  intravenously  into  rabbits. 
Muscular  contractions  were  induced.  Death  followed  in 
one  animal,  which,  in  addition  to  the  above  treatment,  re- 


CHOLERA.  99 

ceived  an  injection  of  a  non-sterilized  culture.  In  this  case 
there  was  observed  an  extensive  calcification  of  the  epithelium 
of  the  urinifcrous  tubules.  Klebs  believes  this  change  in 
the  kidney  to  be  induced  by  the  chemical  poison,  and  from 
this  standpoint  he  explains  the  symptoms  of  cholera  as 
follows :  The  cyanosis  is  a  consequence  of  arterial  contrac- 
tion, the  first  effect  of  the  poison.  The  muscular  contrac- 
tions also  result  from  the  action  of  the  poison.  The  serous 
exudate  into  the  intestines  follows  upon  epithelial  necrosis. 
Anuria  and  the  subsequent  severe  symptoms  appear  when 
the  formation  and  absorption  of  the  poison  become  greatest. 

HuEPPE  states  that  the  severe  symptoms  of  cholera  can 
be  explained  only  on  the  supposition  that  the  bacilli  pro- 
duce a  chemical  poison,  and  that  this  poison  resembles 
muscarine  in  its  action. 

BujwiD  found  that  on  the  addition  of  from  five  to  ten 
per  cent,  of  hydrochloric  acid  to  bouillon  cultures  of  the 
cholera  bacillus,  there  was  developed  after  a  few  minutes  a 
rose-violet  coloration  which  increased  during  the  next  half 
hour  and  in  a  bright  light  showed  a  brownish  shade.  The 
coloration  is  more  marked  if  the  culture  is  kept  at  about 
37°.  In  impure  cultures  this  reaction  does  not  occur. 
The  Finkler-Prior  bacillus  cultures  give  after  a  lono-er 
time  a  similar,  but  more  of  a  brownish  coloration.  Cul- 
tures of  many  other  bacilli  were  tried  and  failed  to  give 
this  reaction. 

Brieger  found  that  this  color  is  due  to  an  indol  deriva- 
tive. In  cholera  cultures  on  albumens  he  obtained  indol 
by  distillation  with  acetic  acid. 

BuJWiD  has  recently  made  a  further  contribution  to  our 
knowledge  of  the  "cholera-reaction."  His  conclusions  are 
as  follows  : 

(1)  Five  to  ten  per  cent,  of  hydrochloric  acid  added  to 


100  PTOMAINES. 

cholera  cultures  produce  a  rose-violet  coloration,  which  is 
characteristic  of  the  comma  bacillus. 

(2)  No  other  bacterium  gives  the  same  coloration  under 
the  same  conditions. 

(3)  The  coloration  appears  in  such  cultures  which  are 
from  ten  to  twelve  hoars  old,  so  that  this  test  can  be  used 
for  diagnostic  purposes,  and  will  give  results  before  they 
can  be  obtained  by  plate  cultures. 

(4)  Impure  cultures  do  not  give  this  reaction. 

DuJSTHAM  finds  the  best  medium  for  the  "  chol era- reac- 
tion" to  be  a  one  per  cent,  alkaline  peptone  solution  with 
one-half  per  cent,  of  common  salt.  Bujwii)  prefers  a  two 
per  cent,  feebly  alkaline  peptone  solution  with  salt.  Jadas- 
sohn finds  that  gelatine  cultures  give  the  reaction  both 
before  and  after  the  liquefaction  of  the  gelatine.  The  un- 
dissolved gelatine,  after  the  addition  of  hydrochloric  or 
sulphuric  acid,  becomes  rose- violet. 

Cohen  claims  that  cultures  of  other  bacilli  give  a  similar 
coloration,  but  Bujwid  explains  that  the  results  obtained 
by  Cohen  were  due  to  the  use  of  impure  acids,  which  con- 
tained nitrous  acid.  Salkowski  agrees  with  Bujwid, 
and  states  that,  when  acids  wholly  free  from  nitrous  acid 
are  used,  the  reaction  is  characteristic  of  the  comma  bacillus. 
He  explains  the  reaction  by  supposing  that  the  germ  pro- 
duces nitrous  acid,  which  exists  in  the  culture  as  a  nitrite. 
On  the  addition  of  an  acid  the  nitrous  acid  is  set  free,  and 
acting  upon  the  indol,  which  is  also  present,  gives  the 
coloration. 

The  reaction  can  also  be  obtained  by  adding  crystallized 
oxalic  acid  to  the  culture. 

ScHUCHARDT  calls  attention  to  the  fact  that  Virchow 
observed  a  red  coloration  on  the  addition  of  nitric  acid  to 
filtered   cholera   stools  forty  years  ago.     Griesinger,  in 


CHOLERA.  101 

1885,  also  made  raention  of  the  productiou  of  a  red  colora- 
tioQ  in  rice-water  stools  on  the  addition  of  nitric  acid. 

A  "cholera-blue"  has  also  been  observed  by  Brieger, 
in  cultures  in  meat  extract  containing  peptone  and  gelatine. 
This  substance,  which  is  yellow  by  reflected,  and  blue  by 
transmitted  light,  is  developed  by  the  addition  of  concen- 
trated sulphuric  acid  to  the  culture.  It  may  be  separated 
from  the  "cholera-red  "  as  follows  :  Treat  the  culture  with 
sulphuric  acid,  then  render  alkaline  with  sodium  hydrate, 
and  extract  with  ether.  Evaporate  the  ether,  and  remove 
the  "cholera-red"  with  benzol,  then  again  dissolve  the 
"cholera-blue"  in  ether.  The  characteristic  absorption 
bands  for  this  coloring  matter  begin  in  the  first  third  of  the 
spectrum,  between  E  and  F,  and  darken  all  of  the  zone 
lying  beyond. 

YiLLiERS  isolated  by  the  Stas-Otto  method  from  two 
bodies  dead  from  cholera,  a  poisonous  base  which  was 
liquid,  pungent  to  the  taste,  and  possessed  the  odor  of  haw- 
thorn. It  was  strongly  alkaline,  and  gave  precipitates  with 
the  general  alkaloidal  reagents.  From  one  to  two  milli- 
grams of  thi.s  substance,  injected  into  frogs,  caused  decreased 
activity  of  the  heart,  violent  trembling,  and  death.  The 
heart  was  found  in  diastole,  and  full  of  blood,  and  the 
brain  slightly  congested.  However,  the  presence  of  this 
substance  in  the  bodies  of  persons  who  have  died  of  cholera 
does  not  prove  that  its  production  is  due  to  the  cholera 
bacillus. 

PouCHET  extracted  from  cholera  stools,  with  chloroform, 
an  oily  base  belonging  to  the  pyridine  series.  It  readily 
reduces  ferric  as  well  as  gold  and  platinum  salts,  and  forms 
an  easily  decomposable  hydrochloride.  It  is  a  violent 
poison,  irritating  the  stomach,  and  retarding  the  action  of 

9* 


102  PTOMAINES. 

the  heart.  Subsequently,  he  obtained  an  apparently  iden- 
tical substance  from  cultures  of  Koch's  comma  bacillus. 

Brieger  has  recently  made  a  report  upon  the  ptomaines 
of  cholera.  He  used  pure  cultures  on  beef-broth  (fleisch- 
brei),  which  was  rendered  alkaline  by  the  addition  of  a 
three  per  cent,  soda  solution.  These  were  kept  at  from 
37°  to  38°.  After  twenty-four  hours,  cadaverine  was 
found  to  be  present.  Older  cultures  furnished  very  small 
quantities  of  putrescine.  The  lecithin  was  slowly  acted 
upon  by  the  germs,  but  with  age  the  amount  of  choline 
increased,  reaching  its  maximum  during  the  fourth  week. 

Creatine  proved  still  more  resistant  to  the  action  of  the 
germs ;  but,  after  six  weeks,,  a  considerable  quantity  of 
creatinine  was  isolated,  and  a  smaller  amount  of  methyl- 
guanidiue.  The  latter  is  very  poisonous,  causing  muscular 
tremors  and  dyspnoea.  The  presence  of  methyl-guanidine 
indicates  that  the  comma  bacillus  acts  as  an  oxidizing  agent, 
since  creatine  yields  methyl-guanidiue  only  by  oxidation. 

Brieger  succeeded  in  finding,  in  addition  to  the  above- 
mentioned  ptomaines,  which  are  common  products  of  putre- 
faction, two  poisons  which  he  considers  as  specific  products 
of  the  comma  bacillus.  One  of  these,  found  in  the  mer- 
curic chloride  precipitate,  is  a  diamine,  resembling  trime- 
thylenediamine.  It  produced  muscular  tremor  and  heavy 
cramps.  In  the  mercury  filtrate  was  found  another  poison, 
which,  in  mice,  produced  a  lethargic  condition  ;  the  respira- 
tion and  heart's  action  became  slow,  and  the  teaiperature 
sank,  so  that  the  animal  felt  cold.  Sometimes  there  was 
bloody  diarrhoea. 

Tetanus. — In  1884,  Nicolaier,  by  inoculating  140 
animals  with  earth  taken  from  different  places,  produced 
symptoms  of  tetanus  in  69  of  them.     In  the  pus  which 


TETANUS.  103 

formed  at  the  point  of  inoculation,  he  found  micrococci  and 
bacilli.  Among  the  latter  was  one  which  was  somewhat 
longer  and  slightly  thicker  than  the  bacillus  of  mouse- 
septicajmia.  In  the  subcutaneous  cellular  tissue  he  found 
this  bacillus  alone,  but  could  not  detect  it  in  the  blood, 
muscles,  or  nerves.  Heating  the  soil  for  an  hour  rendered 
the  inoculations  with  it  harmless.  In  cultures,  Xicolaier 
was  unable  to  separate  this  bacillus  from  other  germs,  but 
inoculations  with  mixed  cultures  produced  tetanus.  In  the 
same  year,  Caiile  and  Ratione  induced  tetanus  in  lower 
animals  by  inoculations  with  matter  takeu  from  a  pustule 
on  a  man  just  dead  from  tetanus.  In  1886,  Ro.sexbach 
made  successful  inoculations  on  animals  with  matter  taken 
from  a  man  who  had  died  from  tetanus  consequent  upon 
gangrene  from  frozen  feet.  With  bits  of  skin  taken  from 
near  the  line  of  demarcation,  he  inoculated  two  guinea-pigs 
on  the  thigh  ;  tetanic  symptoms  .set  in  within  twelve  hours, 
and  one  animal  died  within  eighteen,  and  the  other  within 
twenty-four  hours.  The  symptoms  corresponded  exactly 
with  those  observed  in  the  "  earth  tetanus  "  of  Nicolaier, 
and  the  same  bacillus  was  found.  With  mixed  cultures  of 
this,  Rosexbach  was  also  able  to  cause  death  by  tetanus 
in  animals.  Beumer  had  under  observation  a  man  who 
died  from  lock-jaw  following  the  sticking  of  a  splinter  of 
wood  under  his  finger-nail.  Inoculations  of  mice  and  rab- 
bits with  some  of  the  dirt  found  on  the  wood  led  to 
tetanus.  The  same  observer  saw  a  boy  die  from  this  dis- 
ease following  an  injury  to  the  foot  from  a  sharp  piece  of 
stone.  White  mice  inoculated  with  matter  from  the  wound, 
and  those  inoculated  with  dirt  taken  from  the  boy's  play- 
ground, died  of  tetanus.  The  bacillus  of  Nicolaier  was 
again  detected.  Giordano  reports  the  case  of  a  man  who 
fell  and  sustained  a  complicated  fracture  of  the  arm.     He 


104  PTOilAIXES. 

remained  on  the  ground  for  some  hours,  and  when  assist- 
ance came  the  muscles  and  skin  were  found  torn  and  the 
wounds  filled  with  dirt.  On  the  fifth  day  he  showed  symp- 
toms of  tetanus,  from  which  he  died  on  the  eighth  day. 
Inoculations  and  examinatioas  for  the  bacillus  were  ag-ain 
successful.  Teeeari  also  made  successful  inoculations 
with  the  blood  taken  during  life  from  a  woman  with  tetanus 
after  an  ovariotomy.  Hocksixger  has  confirmed  the 
above-mentioned  observations  by  carefully  conducted  exper- 
iments, the  material  for  which  was  ftirnished  Ijy  a  case  of 
tetanus  arising  from  a  very  slight  injury  to  the  hand,  the 
wound  being  filled  with  dirt.  Shakespeare  has  suc- 
ceeded in  inducing  tetanus  in  rabbits  by  iaoculating  them 
with  matter  taken  from  the  medulla  of  a  horse  and  of  a 
mule,  both  of  which  had  died  from  traumatic  tetanus. 
These  uniform  observations  leave  no  room  to  doubt  that 
tetanus  is  often,  at  least,  due  to  a  germ  which  exists  in 
many  places  in  the  soil,  and  that  the  disease  is  transmissible 
by  inoculation. 

BoNOME  observed  nine  cases  of  tetanus  among  seventy 
persons  injured  by  the  falling  of  a  church  from  the  earth- 
quake at  Bajardo.  The  bacillus  of  ISricxjLAiER  was 
detected  in  the  wounds,  aud  animals  inoculated  with  the 
lime-dust  of  the  fallen  building  died  of  tetanus.  Of  many 
persons  injured  by  the  falling  of  another  church  at  the  same 
time,  none  had  tetanus,  and  animals  inoculated  with  the 
lime  from  this  church  suffered  no  inconvenience. 

The  same  experimenter  found  the  bacillus  in  the  wound 
of  a  sheep  which  died  from  tetanus  after  castration. 

Beumer  found  the  tetanus  bacillus  in  the  sloughing 
tissue  of  the  umbilical  cord  of  a  child  which  was  taken  ill 
on  the  sixth  day  after  birth,  and  died  four  days  later  from 
tetanus.     From  this  he  concludes  tliat  tetanus  neonatorum 


TYPHOID    FEVER.  105 

and  "earth  tetanus  "  are  identical,  and  advises  that  the  cord 
should  be  dressed  antisoptieally. 

The  question  now  arises,  How  do  these  tierms  induce 
tetanus?  Brieger  has  given  us  an  answer  inasmuch  as  lie 
has  obtained  in  cultures  of  the  germ  of  Nicola ier  and 
RosENBAOii  four  poisonous  substances.  The  first,  tetauine, 
which  rapidly  decomposes  in  acid  solutions,  but  is  stable 
in  alkaline  solutions,  produces  tetanus  in  mice  when  in- 
jected in  quantities  of  only  a  few  milligrams.  The  second, 
tetanotoxine,  produces  first  tremor,  then  paralysis  followed 
by  severe  convulsions.  The  third,  to  which  no  name  has 
been  given,  causes  tetanus  accompanied  by  free  flow  of  the 
saliva  and  tears.  The  fourth,  spasmotoxine,  induces  heavy 
clonic  and  tonic  convulsions. 

It  may  be  that  all  these  will  be  found  to  be  modificatious 
or  impure  forms  of  the  same  poison.  Brieger  states 
that  the  exact  character  and  relative  amounts  of  the 
poisons  formed  vary  with  the  nutrient  in  which  the  germ 
grows. 

With  this  evidence  before  us,  we  feel  justified  in  saying 
that  the  tetanus  germ  produces  its  poisonous  effects  by 
elaborating  one  or  more  ptomaines  in  the  body  of  the 
animal  into  which  it  has  been  introduced. 

Typhoid  Fever.  —  This  disease  also  illustrates  the 
definition  "  which  we  have  given  of  an  infectious  disease. 
In  1880,  Eberth  discovered  a  bacillus  which  he  believed 
to  be  the  cause  of  typhoid  fever,  and  this  belief  has  been 
confirmed.  The  fever,  with  its  characteristic  lesions,  has 
been  produced  in  animals  by  inoculation  with  the  germ. 
Gaffky  was  the  first  to  inoculate  animals  with  pure  cul- 
tures of  the  bacillus  of  Eberth,  but  his  results  were 
wholly  negative.    Frankel  and  Simmonds  produced  fatal 


106  PTOMAINES. 

results  and  observed  after  death  enlargemeut  of  the  spleen, 
mesenteric  glands,  and  intestinal  follicles.  Moreover, 
microscopical  examination  of  the  spleen  showed  the  same 
conditions  which  are  found  in  the  spleen  of  persons  dead 
of  typhoid  fever.  Seitz,  using  Koch's  method  of  cholera 
inoculation,  produced  with  the  typhoid  bacillus  acute  ente- 
ritis, with  ulceration  and  enlargement  of  the  spleen. 
Vaughax  and  Xoyy,  using  the  germ  which  they  had 
obtained  from  drinking  water,  produced  in  a  cat  vomiting, 
great  muscular  weakness  or  prostration,  primary  depression 
of  temperature  four  degrees  below  the  normal,  and  secondary 
elevation  of  temperature  three  degrees  above  the  normal. 
Section  showed  ulceration  in  both  the  small  intestine  and 
ascending  colon.  Results  of  this  kind  leave  no  doubt  that 
the  bacillus  first  described  by  Eberth  is  the  true  germ  of 
typhoid  fever. 

In  1885,  Beieger  obtained  from  pure  cultures  of  the 
typhoid  bacillus  a  toxic  ptomaine,  which  produced  in 
guiuea-pigs  a  slight  flow  of  saliva,  frequency  of  respira- 
tion, dilatation  of  the  pupils,  profuse  diarrhoea,  paralysis, 
and  death  within  from  twenty-four  to  forty-eight  hours. 
Post-mortem  examination  showed  the  heart  in  systole,  the 
lungs  hypersemic,  and  the  intestines  contracted  and  pale. 
This  substance  Brieger  considers  the  special  poison  of 
typhoid  fever,  and  calls  it  typhotoxine.  However,  he 
obtained  with  this  poison  no  elevation  of  temperature. 

In  1887,  Vaughax  and  Noyy  obtained  from  pure 
cultures  of  the  typhoid  bacillus,  found  in  drinking  water 
which  had  been  the  supply  for  many  persons  who  had  the 
disease,  an  extract  which,  when  injected  under  the  skin  of 
cats,  caused  an  elevation  in  the  temperature  of  from  two 
to  four  and  one-half  degrees  above  the  normal. 

SiROTixiN  and  Beumer  and  Peiper  have  produced  the 


CHOLERA    INFANTUM.  107 

same  pathologiciil  phenomena  by  inoculating  animals  with 
sterilized  cultures  that  they  obtained  with  the  germ.  They 
found  that  the  severity  of  the  symptoms  varied  with  the 
amount  of  the  culture  injected. 

In  one  sick  of  typhoid  fever,  the  bacillus  grows  and 
multiplies  in  the  intestines  and  forms  the  poison,  the  ab- 
sorption of  which  is  followed  by  the  rise  in  temperature 
and  other  symptoms  of  the  disease.  The  lesions  in  the 
intestines  are  probably  due  to  the  bacteria  themselves,  or 
possibly  to  the  local  irritating  effect  of  the  ptomaine. 

Cholera  Infantum. — There  are  many  reasons  for 
believing  that  this  disease  is  sometimes  at  least  due  to 
poisoning  by  tyrotoxicon.  The  fact  that  infants  nourished 
exclusively  from  the  mother's  breast  are  almost  wholly 
exempt  from  the  disease  strengthens  this  belief  We  have 
already  seen  how  quickly  and  abundantly  this  poison 
appears  in  milk  when  the  conditions  are  favorable.  More- 
over, the  symptoms  induced  by  the  poison  agree  with  those 
observed  in  the  disease,  and  the  post-mortem  changes  are 
identical.  Cholera  infantum  is  a  disease  of  the  summer 
months,  when  decomposition  in  milk  goes  on  most  readily. 
It  is  most  common  in  cities  and  among  classes  who  cannot 
obtain  fresh  milk  or  have  not  the  means  necessary  to  keep 
it  fresh.  Moreover,  it  is  often  allowed  to  stand  in  a  foul 
atmosphere,  and  all  know  that  milk  readily  takes  up  dis- 
agreeable odors.  Even  in  the  country,  insufficient  atten- 
tion is  given  to  the  care  of  milk.  Cows  stand  and  are 
milked  in  filthv  barns.  The  udders  are  generallv  not 
washed  before  the  milking,  and  the  vessels  for  the  milk 
are  frequently  not  as  clean  as  they  should  be.  There  can 
be  no  doubt  that  greater  attention  to  the  milk  used  by 


108  PTOMAINES. 

infants   woulJ   result   in  saving  many  thousands  of  lives 
annually. 

Puerperal  Fever. — Bourget  claims  to  have  isolated 
several  ptomaines  from  the  urine  of  women  with  puerperal 
fever.  His  conclusions  are  as  follows  :  (1)  In  puerperal 
fever  the  urine  contains  highly  poisonous  bases.  (2)  The 
toxicity  of  the  urine  is  most  marked  when  the  symptoms 
of  the  disease  are  most  grave,  and  diminishes  as  the  symp- 
toms abate.  (3)  The  ptomaines  obtained  from  the  urine 
prove  fatal  when  injected  into  frogs  and  guinea-pigs.  (4) 
Toxic  bases,  resembling  those  obtained  from  the  urine,  were 
extracted  from  the  viscera  of  a  woman  who  had  died  of 
puerperal  fever. 

Immunity  from  Disease  secured  by  Intoxication 
WITH  Ptomaines. — Salmon  and  Smith  ascertained  that 
pigeons  may  be  protected  from  the  fatal  effects  which  ordi- 
narily follow  inoculation  with  cultures  of  the  hog  cholera 
bacillus  by  first  injecting  into  their  tissues  two  doses  of  one 
cubic  centimeter  each  of  a  culture  liquid  in  which  the  microbe 
had  been  allowed  to  multiply  and  had  afterward  been  de- 
stroyed by  heat.  In  other  words,  they  found  that  injection 
of  the  ptomaine  conferred  immunity  from  the  effects  of  the 
living  germ.  However,  they  have  been  unable,  up  to  the 
present  time,  to  secure  immunity  from  the  disease  in  hogs 
by  this  method. 

Chantemesse  and  Vidal,  and  others,  have  found  that 
severe  intoxication  of  animals  with  sterilized  cultures  of 
the  typhoid  bacillus  protects  against  subsequent  inoculation 
with  the  germs.  This  has  led  to  the  supposition  that  man 
might  be  protected  from  this  disease  by  the  same  method. 

Roux  and  Chamberland  have  recently  shown   that 


INTOXICATION    WITH     PTOMAINES.  109 

injections  of  sterilized  cultures  of  the  germ  of  septieseraia 
{laaUgnant  cedcma  of  Kocir  and  Gaffky ,  f/aiu/renc  f/dzeiise 
of  Chauveau  and  Arloing)  give  iniiuunity  from  the 
effects  of  the  living  germ,  as  is  })roven  by  subsequent 
inoculation. 

Pasteur  is  inclined  to  the  belief  that  the  protection 
which  he  secures  against  hydrophobia  is  due  to  the  action 
of  a  chemical  substance,  or  a  ptomaine,  and  not  to  a  living 
germ.  Pasteur  and  Perdrix  have  made  some  experi- 
ments which  go  to  show  that  the  injection  of  sterilized 
anthrax  blood  affords  protection  against  subsequent  inocu- 
lation with  the  bacillus  authracis  in  rabbits. 

These  experiments  are  of  the  greatest  value.  However, 
it  is  too  early  yet  to  assert  that  the  immunity  thus  secured 
by  intoxication  with  ptomaines  is  identical  with  that  secured 
against  smallpox  by  vaccination.  Grant  that  Pasteue  is 
right  in  supposing  that  his  method  of  securing  immunity 
against  hydrophobia  is  due  to  a  chemical  substance  and  not 
to  a  living  organism  (and  we  think  his  method  is  most 
rationally  explained  in  this  way),  then  the  question  arises, 
Has  he  really  vaccinated  the  person  against  hydrophobia,  or 
has  he  simply  established  a  tolerance  for  the  poison  of 
hydrophobia?  The  period  of  continuance  of  the  immunity 
should  be  determined.  Sewall  found  that  he  could  estab- 
lish a  tolerance  for  the  venom  of  the  rattlesnake  in  pigeons, 
but  after  six  mouths  the  tolerance  was  lost. 


10 


CHAPTER    lY. 

THE  IMPOETANCE  OF  PTOMAINES  TO  THE  TOXICOjiiOGIST. 

The  presence  in  the  cadaver  of  substances,  which  give  not 
only  the  general  alkaloidal  reactions  but  respond  to  some  of 
the  tests  which  have  hitherto  been  considered  characteristic 
of  individual  vegetable  alkaloids,  must  be  of  the  greatest 
importance  to  toxicologists.  The  possibility  of  mistaking 
putrefactive  for  vegetable  alkaloids  should  always  be  borne 
in  mind  by  the  chemist  in  making  his  medico-legal  investi- 
gations. On  the  other  hand,  as  we  have  seen  in  preceding 
chapters,  cases  of  poisoning  by  ptomaines  sometimes  termi- 
nate fatally,  and  in  such  instances  the  chemist  should  not 
be  satisfied  with  determining  the  absence  of  mineral  and 
vegetable  poisons,  but  should  strive  to  detect  in  the  food 
or  in  the  dead  body  positive  evidence  of  the  presence  of 
the  putrefactive  alkaloid. 

In  this  chapter  we  will  give  an  account  of  those  cases  in 
which  putrefactive  substances  have  been  found  to  resemble 
in  their  reactions  the  vegetable  alkaloids. 

CoNiiXE-LiKE  Substances. — The  most  celebrated  case 
in  which  a  substance  giving  reactions  similar  to  those  of 
coniine  has  been  found,  was  the  Brandes-Krebs  trial,  which 
took  place  in  Braunschweig  in  1874.  From  the  undecom- 
posed  parts  of  the  body  two  chemists  obtained,  in  addition 
to  arsenic,  an  alkaloid  which  they  pronounced  coniine.  This 
substance  was  referred  to  Otto  for  further  examination. 
Otto  reported  that  the  substance  was  neither  coniine  nor 


CONIINE-LIKE    SUBSTANCES.  Ill 

nicotiue,  nor  any  ve^^etable  alkaloid  with  wliich  he  was 
acquainted.  Otto  converted  the  substance  into  an  oxalate, 
dissolved  it  in  alcohol,  evaporated  the  alcohol,  dissolved 
the  residue  in  water,  rendered  this  solution  alkaline  with 
potash,  then  extracted  the  base  with  petroleum  ether.  On 
evaporation  of  the  petroleum  ether  the  alkaloid  appeared  as 
a  bright  yellow  oil,  which  had  a  strong,  unpleasant  odor, 
quite  different,  however,  from  that  of  coniine.  It  was 
strongly  alkaline  and  had  an  intensely  bitter  taste.  At 
ordinary  temperature,  it  was  volatile.  From  its  aqueous 
solution  it  was  precipitated  l)y  the  chlorides  of  gold,  plati- 
num, and  mercury.  In  these  reactions  it  resembled  nico- 
tine, from  which  it  differed  in  the  double  refractive  and 
crystalline  character  of  its  hydrochloride.  With  an  ethereal 
solution  of  iodine  this  substance  did  not  give  the  RoussiN 
test  for  nicotine,  but  instead  of  the  long  ruby-red  crystals, 
there  appeared  small,  dark  green,  needle-shaped  crystals. 

This  substance  was  found  to  be  highly  poisonous.  Seven 
centigrams  injected  subcutaneously  into  a  large  frog  pro- 
duced instantaneous  death,  and  forty-four  milligrams  given 
to  a  pigeon  caused  a  similar  result.  On  account  of  its 
poisonous  properties  the  jury  of  medical  experts  decided 
that  the  substance  was  a  vegetable  alkaloid.  Otto  says 
that  this  decision  astounded  the  chemists. 

Brouaedel  and  Boutmy  found  in  the  body  of  a  woman 
who  had  died,  after  suffering  with  ten  other  persons,  from 
choleraic  symptoms  from  eating  of  a  stuffed  goose,  a  base 
which  gave  the  odor  of  coniine  and  the  same  reactions  with 
gold  chloride  and  iodiue  in  potassium  iodide,  etc.,  as  coniine. 
The  same  base  was  found  in  the  remainder  of  the  goose. 
But  it  did  not  give  a  red  coloration  with  the  vapor  of 
hydrochloric   acid,  and   it   did  not  form    butvric  acid  on 


112  PTOMAINES. 

oxidation,  and  although  it  was  poisonous,  it  did  not  pro- 
duce in  frogs  the  symptoms  of  couiiue  poisoning, 

Selmi  repeatedly  found  coniine-like  substances  in  decom- 
posing animal  tissue.  By  distilling  an  alcoholic  extract 
from  a  cadaver,  acidifying  the  distillate  Avith  hydrochloric 
acid,  evaporating,  treating  the  residue  with  barium  hydrate 
and  ether,  and  allowing  the  ether  to  evaporate  spontane- 
ously, he  obtained  a  residue  of  volatile  bases,  the  greater 
part  of  which  consisted  of  trimethylamine.  After  remov- 
ing the  trimethylamine,  the  residue  had  the  odor  of  the 
urine  of  the  mouse.  Later,  Selmi  obtained  an  unmistak- 
able coniine  odor  from  a  chloroform  extract  of  the  viscera 
of  a  person  who  had  been  buried  six  months,  and  in  another 
case  ten  months  after  burial.  Two  or  three  drops  of  an 
aqueous  solution  of  the  alkaline  residue  of  the  chloroform 
extract  allowed  to  evaporate  on  a  glass  plate  gave  oif  such 
a  penetrating  odor  that  Selmi  was  compelled  to  withdraw 
from  close  proximity  with  the  substance.  The  odor  im- 
parted to  his  hands  in  testing  the  substance  with  the  general 
alkaloidal  reagents  remained  for  half  an  hour.  This  volatile 
base  seemed  to  be  formed  by  the  spontaneous  decomposition 
of  other  ptomaines. 

An  aqueous  solution  of  a  ptomaine  obtained  by  Selmi  by 
extraction  with  ether  according  to  the  Stas-Otto  method 
from  the  undecomposed  parts  of  a  cadaver  had  no  marked 
odor,  but  after  having  been  kept  for  a  long  time  in  a  sealed 
tube  it  not  only  gave  off  a  marked  coniine  odor,  but  the 
vapor  turned  red  litmus  paper  blue.  Again,  the  sulphate 
of  a  ptomaine  obtained  from  putrid  egg-albumen  formed  on 
standing  in  two  layers,  one  of  which  was  a  golden-yellow 
liquid,  which,  on  being  treated  with  barium  hydrate,  gave 
oif  ammonia,  and  later,  the  odor  of  coniine.  Since  butyric 
and  acetic  acids  were  formed  by  the  oxidation  of  this  base, 


A    NICOTINE-LIKE    SUBSTANCE.  113 

Selimi  concluded  that  he  had  real  coniiue  or  methylconiine, 
and  that  it  was  formed  by  the  oxidation  of  certain  fixed 
ptomaines,  or  by  the  action  of  different  amido-bases  on 
volatile  fatty  acids.  Therefore,  SkliSII  believed  in  the  spon- 
taneous origin  of  coniine  or  closely  allied  bases  in  putrid 
matter,  also  in  the  existence  of  a  "cadaveric  coniine." 

The  substance  which  was  found  by  Sonnenschein  in  a 
criminal  trial  in  East  Prussia,  and  which  was  believed  by 
that  chemist  to  be  the  alkaloid  of  the  water  hemlock  (cicuta 
virosa),  is  thought  by  Otto,  IIusemann,  and  others,  to  be 
a  cadaveric  coniine.  Otto  says  that  the  symptoms  reported 
in  the  case  were  not  those  of  either  coniine  or  cicuta.  Son- 
nenschein obtained  the  base  six  weeks  after  the  exhuming 
of  the  body,  which  had  been  buried  three  mouths.  The 
base  had  the  odor  of  coniine,  the  taste  of  tobacco,  gave  with 
potassium  bichromate  and  sulphuric  acid  the  odor  of  butyric 
acid,  and  behaved  with  reagents  like  coniine. 

HusEMANN  states  that  at  present  it  is  very  difficult,  if 
not  impossible,  for  the  chemist  to  state  with  certainty  that  he 
has  detected  true  coniine  in  the  dead  body.  The  symptoms 
and  the  post-mortem  appearances  must  conform  with  those 
induced  by  the  vegetable  alkaloid.  The  analysis  must  be 
made  before  decomposition  sets  in,  and  the  amount  of  the 
base  found  must  be  sufficient  for  physiological  experiments 
to  be  made  with  it. 

A  NiCOTINE-LIKE  SuBSTANCE. — WOLCKENHAAR  ob- 
tained from  the  decomposed  intestines  of  a  woman  who  had 
been  dead  six  weeks,  by  extraction  with  ether  from  an 
alkaline  solution,  a  base  which  bore  a  close  resemblance  to 
nicotine.  The  base  was  fluid,  at  first  yellow,  but  on  being 
exposed  to  the  air,  brownish-yellow.  It  was  strongly  alka- 
line in  reaction  and  gave  off  an  odor  resembling  nicotine, 

10* 


114  PTOMAINES. 

but  stroDger,  not  ethereal,  but  benumbing  and  similar  to  that 
of  fresh  poppy-heads.  It  was  soluble  in  all  proportions  in 
water,  and  the  solutions,  which  did  not  become  cloudy  on 
the  application  of  heat,  did  not  taste  bitter,  but  were  slightly 
pungent.  The  peculiar  odor  did  not  disappear  on  saturat- 
ing the  base  with  oxalic  acid.  The  hydrochloride  was 
yellow,  like  varnish,  had  a  strong  odor,  and  became  moist 
on  exposure  to  the  air.  Under  the  microscope  it  showed 
no  crystals,  diifering  in  this  respect  from  nicotine  hydro- 
chloride. It  differed  from  nicotine  also  in  its  reactions 
with  potassio-bisrauthic  iodide,  gold  chloride,  iodine  solu- 
tion, mercuric  chloride,  and  platinum  chloride.  It  also 
failed  to  give  the  Roussin  test  for  nicotine.  Moreover,  it 
could  not  be  identified  with  trimethylamine,  sparteine, 
mercurialine,  lobeline,  or  other  fluid  and  volatile  bases. 

The  studies  of  Rorsch  and  Fassbender  (page  25),  of 
ScHWANERT  (page  26),  of  LiEBERMANN  (page  27),  and  of 
Selmi  (page  28),  have  already  been  referred  to  in  a  pre- 
ceding chapter. 

Strychnine-like  Substances. — In  a  criminal  prose- 
cution at  Verona,  Ciotta  obtained  from  the  exhumed,  but 
only  slightly  decomposed  body,  an  alkaloid  which  gave  a 
crystalline  precipitate  with  iodine  in  hydriodic  acid,  a  red 
coloration  with  hydriodic  acid,  and  a  color  test  similar  to 
that  of  strychnine  with  sulphuric  acid  and  potassium 
bichromate,  and  with  other  oxidizing  agents.  This  sub- 
stance was  strongly  poisonous,  but  did  not  produce  the 
tetanic  convulsions  which  are  characteristic  of  strychnine. 
Ciotta  pronounced  this  substance  as  probably  identical 
with  strychnine.  Portions  of  the  body  were  subsequently 
submitted  to  Selmi  for  his  opinion.  Selmi  found  that  the 
substance  which  gave  the  color  reaction  was  not  crystalline. 


A    MORPHINE-LIKE    SUBSTANCE.  115 

and  tliat  tlicro  was  only  "  the  presumption  of  a  bitter  taste 
to  it,"  while  one  part  ot"  strychnine  in  40,000  parts  of  water 
is  intensely  bitter.  Selmi  also  held  that  many  ptomaines 
give  reactions  similar  to  strychnine  with  iodine  in  hydriodic 
acid,  and  with  hydriodic  acid.  He  also  held  that  its  physi- 
ological properties  were  such  that  it  could  not  be  strych- 
nine. This  substance  could  hardly  have  been  aspidosper- 
mine,  which  reacts  with  sulphuric  acid  and  potassium 
bichromate  similar  to  strychnine,  because  quebracho  bark, 
in  which  this  alkaloid  is  found,  was  not  at  that  time  used 
as  a  medicine  or  known  in  Italy. 

Ptomaines  giving  reactions  similar  to  those  of  strychnine, 
and  also  causing  tetanic  spasms,  have  been  found  in  Italy 
in  decomposed  corn-meal.  Selmi  obtained  one  of  these 
substances,  but  found  that  it  differed  from  strychnine  inas- 
much as  it  could  not  be  extracted  with  ether. 

LoJiBROSO  has  named  the  poisonous  substance  found  in 
decomposed  corn-meal  pellagroceine,  but  this  is  really  a 
mixture  ot  ptomaines,  some  of  which  produce  narcosis  and 
paralysis,  and  others  produce  the  symptoms  of  nicotine 
poisoning  instead  of  the  spasms  caused  by  strychnine. 

A  Morphine-like  Substance. — In  the  Sonzogna  trial, 
at  Cremona,  Italy,  the  experts  seem  to  have  confounded  a 
ptomaine  with  morphine.  This  substance  was  not  removed 
from  either  alkaline  or  acid  solutions  with  ether,  but  could 
be  extracted  with  amy  lie  alcohol.  It  reduces  iodic  acid,  but 
in  its  other  reactions,  as  w^ell  as  in  ils  physiological  jjrop- 
erties,  it  bore  no  resemblance  to  morphine.  In  frogs  it 
arrested  the  heart  in  systole,  which  is  said  never  to  happen 
in  poisoning  with  morphine.  It  failed  to  give  both  the 
ferric  chloride  and  the  Pellagri  tests  for  morphine. 

In  the  same  body  there  was  found  a  substance  Avhich  was 


116  PTOMAINES, 

extracted  from  alkaline  solutions  with  ether,  and  which 
gave,  with  hydrochloric  acid  and  a  few  drops  of  sulphuric 
acid,  on  the  apj)licatiou  of  heat,  a  reddish  residue  similar  to 
that  obtained  by  the  same  reagents  with  codeine,  but  in  its 
other  reactions  it  did  not  resemble  this  alkaloid. 

Ateopine-like  Substances. — Many  investigators  have 
found  products  of  putrefaction  which  in  their  mydriatic 
properties  resemble  atropine  and  hyoscyamine.  To  this 
class  belongs  the  substance  observed  by  Zdelzer  aud  Son- 
NENSCHEIN.  It  was  removed  from  alkaline  solutions  by 
ether,  and  formed  microscopic  crystals,  an  aqueous  solution 
of  which,  when  applied  to  the  conjunctiva,  produced  a 
mydriatic  effect,  and,  when  administered  internally,  increased 
the"  action  of  the  heart  and  arrested  the  movements  of  the 
intestines.  Moreover,  with  certain  alkaloidal  reagents,  such 
as  platinum  chloride,  it  resembled  atropine.  But  when 
heated  with  sulphuric  acid  and  oxidizing  agents  it  did  not 
give  the  odor  of  blossoms  (Reuss's  test).  However,  Selmi 
found  ptomatropines  which  with  sulphuric  acid  and  oxidiz- 
ing agents  did  give  the  blossom  odor  as  distinctly  as  the 
vegetable  atropine.  These  putrefactive  bases  also  developed 
this  odor  spontaneously  after  standing  for  two  or  three 
days,  aud  this  does  not  happen  with  atropine.  The  odor 
was  produced  with  the  ptomatropines  by  nitric  and  sulphuric 
acids,  both  in  the  cold  and  on  the  application  of  heat,  while 
these  acids  in  the  cold  do  not  produce  the  odor  with 
atropine. 

Digitaline-like  Substances. — Elsewhere  we  have 
referred  to  the  discovery  of  a  ptomaine  belonging  to  this 
class  by  Rorsch  and  Fassbender  (see  page  26).  Trot- 
tarelli  obtained  a  similar  substance  from  the  brain  of  a 


A    DELPHININE-LIKE    SUBSTANCE.  117 

mau  ill  whoso  tilxlominal  viscera  he  could  iiiul  no  poison. 
The  snl[)liatc  of  this  base  gave  on  evaporation  an  aroniatic- 
snielling-  and  astringent-tasting  residue.  It  became  purple 
with  sul})huric  acid  alone,  and  dark  red  with  hydrochloric 
and  sulphuric  acids.  On  frogs  this  ptomaine  showed  no 
toxic  etfect. 

A  Veratrine-i.ike  Substance. — Brouardel  and 
BoUTA[Y  obtained  from  a  corpse  which  had  lain  in  water 
for  eighteen  months,  and  a  large  portion  of  which  had 
changed  into  adipocere,  a  ptomaine  resembling  veratriue. 
It  was  removed  from  alkaline  solutions  by  ether.  On 
being  heated  with  sulphuric  acid  it  became  violet.  With 
a  mixture  of  sulphuric  acid  and  barium  peroxide  it  be- 
came, in  the  cold,  brick-red;  and,  on  being  heated,  violet. 
With  boiling  hydrochloric  acid  it  took  on  a  cherry-red 
coloration.  However,  it  differed  from  veratriue,  inasmuch 
as  it  reduced  ferric  salts  instantly,  and  when  injected  into 
frogs  subcutaneously  it  did  not  induce  in  them  the  spas- 
modic muscular  contractions  characteristic  of  veratriue. 

Becfiamp  obtained  by  the  Stas-Otto  method  from  the 
products  of  the  pancreatic  digestion  of  fibrin  an  alkaloid 
body  which  gave  with  sulphuric  acid  a  beautiful  carmine- 
red,  similar  to  that  given  with  veratriue.  By  digesting  this 
substance  with  gastric  juice,  and  again  extracting,  he 
obtained  a  body  which  behaved  with  sulphuric  acid  similar 
to  curarine. 

A  Deephinine-like  Substance. — In  1870,  General 
Gibbone,  an  Italian  of  prominence,  died  suddenly.  His 
servant  was  accused  of  having  poisoned  him.  Two  chem- 
ists of  some  reputation  reported  the  presence  of  delphinine 
in  the  viscera.     It  seemed  somewhat  improbable  that  the 


118  PTOMAINES. 

servant  should  know  anything  of  so  rare  a  substance,  or 
that  he  should  have  been  able  to  obtain  it.  However,  t^vo 
or  more  varieties  of  staphisagria  grow  in  Southern  Italy, 
and  it  was  possible  that  the  servant  had  used  some  prepara- 
tion made  by  himself  from  the  plant.  The  supposed  alka- 
loid was  given  to  Sp:lmi,  of  Bologna,  for  further  study.  It 
was  removed  from  alkaline  solutions  by  ether.  When 
heated  with  phosphoric  acid  it  became  red,  and  when 
brought  in  contact  with  concentrated  sulphuric  acid,  reddish- 
brown.  In  these  tests  the  substance  resembled  delphinine, 
but  with  sulphuric  acid  and  bromine  water,  also  with 
Feohde's  reagent,  the  colorations  characteristic  of  the 
vegetable  alkaloid  failed  to  appear.  Moreover,  Selmi 
showed  that  delphinine  gave  the  following  reactions,  to 
which  the  suspected  substance  did  not  respond  :  (1)  Delph- 
inine dissolved  in  ether,  and  treated  with  a  freshly  prepared 
ethereal  solution  of  platinic  chloride,  gives  a  white,  floccu- 
lent  precipitate  which  is  insoluble  in  an  equal  volume  of 
absolute  alcohol.  (2)  Delphinine  gives  precipitates  with 
auro-sodium  hyposulphite,  and  with  a  sulphuric  acid  solu- 
tion of  cupro-sodium  hyposulphite,  the  latter  precipitate 
being  soluble  in  an  excess  of  the  reagent. 

Finally,  CiACCiA  and  Vella  showed  tliat  while  delph- 
inine arrests  the  heart  of  the  frog  in  diastole,  the  suspected 
substance  arrests  it  in  systole. 

A  CoLCHiciNE-LiKE  SuBSTANCE. — Baumert  found  in 
a  suspected  case  of  poisoning,  twenty-two  months  after 
death,  a  substance  which  gave  many  of  the  reactions  for 
colchicine.  It  was  extracted  from  acid  solutions  with  ether, 
to  which  it  imparted  a  yellow  color.  On  evaporation  of 
the  ether  a  yellow,  amorphous  substance  remained,  and 
this  dissolved  in  warm  water  with  yellow  coloration.     It 


A    COLCHICINE-LIKE    SUBSTANCE.  119 

could  be  extracted  from  acid  solutions  also  by  chloroform, 
benzol,  and  uniylic  alcohol,  but  not  by  petroleum  ether.  It 
was  removed  with  much  more  ditliculty  from  alkaline 
solutions. 

All  the  extracts  were  yellow,  and  left  on  evaporation  a 
feebly  alkaline,  markedly  bitter,  sharp  tasting,  amorphous, 
yellow  residue,  which  dissolved  in  water  and  dilute  acids 
incompletely,  forming  a  resin.  When  this  resin  was  dis- 
solved in  dilute  sodium  hydrate,  and  the  solution  rendered 
acid  by  sulphuric  acid,  the  same  reactions  were  obtained  as 
with  the  original  extract. 

With  phosphomolybdic  acid,  phosphotungstic  acid,  potas- 
sio-bismuthic  iodide,  potassio-mercuric  iodide,  iodine  in 
potassium  iodide,  tannic  acid  and  gold  chloride,  this  sub- 
stance gave  the  same  reactions  which  were  obtained  by 
parallel  experiments  with  genuine  colchicine ;  thus,  the 
tannic  acid  precipitates  were  both  soluble  in  alcohol,  and 
the  precipitates  with  phosphomolybdic  acid  in  both  cases 
became  blue  on  the  addition  of  ammonium  hydrate. 

Concentrated  sulphuric  and  dilute  nitric  and  hydrochloric 
acids  dissolved  the  supposed  colchicine  with  yellow  color- 
ation. Strong  nitric  acid  (1.4  sp.  gr.)  colored  the  substance 
dirty  red,  scarcely  to  be  called  a  violet.  When  the  sub- 
stance was  purified  as  much  as  possible,  this  color  became 
a  beautiful  carmine-red.  The  addition  of  water  changed 
the  red  into  yellow,  and  caustic  soda  produced  a  dark,  dirty 
orange. 

In  general,  in  the  above-mentioned  reactions,  the  putre- 
factive product  agreed  with  the  real  colchicine,  but  the 
former  gave  precipitates  with  picric  acid  and  platinum 
chloride,  while  the  latter  gives  .no  precipitates  with  these 
reagents. 

In  1886,  Zeisel  proposed  the  following  test  for  colchi- 


120  PTOMAINES. 

cine  :  When  a  hydrochloric  acid  solution  of  the  alkaloid  is 
boiled  with  ferric  chloride,  it  becomes  green,  sometimes 
dark  green  and  cloudy.  Now,  if  the  fluid  be  agitated  with 
chloroform,  the  chloroform  will  sink,  taking  up  the  coloring 
matter,  and  appearing  brownish,  granite-red  or  dark,  and 
the  supernatant  fluid  clears  up  without  becoming  wholly 
colorless. 

Baumert  applied  this  test  to  both  colchicine  and  the 
putrefactive  product.  To  from  two  to  five  cubic  centi- 
metres of  the  suspected  solution  in  a  test-tube,  he  added 
from  five  to  ten  drops  of  strong  hydrochloric  acid,  and  from 
four  to  six  drops  of  a  ten  per  cent,  solution  of  ferric 
chloride,  then  heated  the  mixture  directly  over  a  small 
flame  until  it  was  evaporated  to  half  its  volume  or  less.  In 
the  presence  of  one  milligram  of  colchicine  the  originally 
bright  yellow  solution  became  gradually  olive-green,  and, 
on  further  concentration,  dark  green  and  cloudy.  Then, 
on  shaking  the  fluid  with  chloroform,  admitting  as  much 
air  as  possible,  the  chloroform  subsided,  having  a  ruby-red 
color  if  as  much  as  two  milligrams  of  colchicine  were 
present,  and  a  bright  yellow  if  only  one  milligram,  and  the 
supernatant  fluid  became  of  a  beautiful  olive-green.  When 
ether,  petroleum  ether,  benzol,  carbon  disulphide,  or  amy  lie 
alcohol  was  substituted  for  the  chloroform,  the  coloration 
did  not  appear.  From  this  Baumert  infers  that  the  red 
coloring  matter  is  either  only  soluble  in  chloroform,  or  that 
it  is  not  formed  until  the  chloroform  is  added. 

Baumert  found  this  test  of  great  value  in  deciding 
whether  or  not  the  substance  which  he  found  was  colchi- 
cine. The  putrefactive  product  did  not  respond  to  the 
test. 

Some   of   this   substance   was   sent   to   Brieger,    who 


MORPHINE.  121 

decided  that  it  was  not  a  base,  but  a  peptoue-like  substance. 
It  was  also  found  to  be  inert  physiologically. 

Before  these  investigations  were  made  by  Baumert, 
LiEBERMANN  had  fouud  the  same  or  a  similar  colchicine- 
like  substance  in  the  cadaver.  His  description  diifered 
from  that  of  Baumert  only  in  regard  to  the  taste  of  the 
substance,  Liebermanx  having  failed  to  observe  any 
marked  taste  in  the  substance  which  he  found,  while,  as  has 
been  stated,  Baumert  reporter!  a  distinctly  bitter  taste. 

A  colc'hicine-like  substance  has  been  fouud  in  beer,  and 
it  has  been  suggested  that  it  Avas  this  which  the  above- 
mentioned  toxicologists  found  in  the  bodies  which  they 
examined,  but  Liebermanx  states  that  the  man  whose 
body  he  examined  had  been  a  total  abstainer  from  beer. 

Tamba  compared  the  reactions  of  ptomaines  obtained 
from  putrid  sausage  with  similar  reactions  of  various  alka- 
loids, and  then  ascertained  the  effect  upon  the  alkaloidal 
reactions  by  mixing  the  alkaloids  with  the  ptomaines.  His 
results  are  as  follows  : 

Morphine. — Ptomaines  are  colored  yellow  with  nitric 
acid ;  reddish-yellow  with  concentrated  sulphuric  acid ; 
blue,  violet,  then  green  with  Frohde's  reagent ;  yellow 
when  evaporated  with  concentrated  sulphuric  acid,  then 
treated  with  hydrochloric  acid  and  decomposed  with  sodium 
bicarbonate.  The  ptomaines  reduce  ferric  chloride,  but  not 
iodic  acid.  With  sugar  and  concentrated  sulphuric  acid, 
they  give  a  yellow  coloration. 

Mixtures  of  the  ptomaines  and  morphine  give  absolutely 
characteristic  reactions  for  morphine  with  sugar  and  sul- 
phuric acid,  the  violet  coloration  appearing  distinctly  ;  and 
by  evaporation  on  the  water-bath  with  sulphuric  acid,  addi- 

11 


122  PTOMAINES. 

tion  of  hydrochloric  acid  and  decomposition  with  sodium 
bicarbonate,  the  violet  color  appearing.  Iodic  acid  is  re- 
duced by  morphine  in  the  presence  of  ptomaines,  only 
when  the  ptomaines  are  present  in  minute  quantity. 

The  other  reactions  for  morphine  are  not  applicable  in 
the  presence  of  ptomaines. 

Strychnine. — The  characteristic  color  reaction  for  this 
alkaloid,  with  potassium  bichromate  and-  sulphuric  acid,  is 
not  affected  by  the  presence  of  ptomaines.^ 

Brucine. — The  nitric  acid  reaction  for  brucine  is  not 
affected  by  j^tomaiues.  On  the  other  hand,  the  reaction 
with  sulphuric  and  nitric  acids,  in  which  a  red  coloration 
is  obtained,  is  scarcely  visible  in  the  presence  of  ptomaines. 
The  action  of  mercuric  nitrate  and  heat  on  brucine,  by  which 
a  violet  coloration  is  produced,  is  not  destroyed  by  the 
presence  of  ptomaines. 

Veratrine. — The  characteristic  coloration  of  veratrine 
by  concentrated  sulphuric  acid  is  not  influenced  by 
ptomaines.  The  same  is  true  of  the  cherry-red  coloration 
with  concentrated  hydrochloric  acid.  On  the  contrary,  the 
action  of  sugar  and  sulphuric  acid  on  veratrine  is  without 
result  in  the  presence  of  ptomaines. 

Atropine.  —  The  deep  violet  coloration  produced  by 
fuming  nitric  acid,  subsequent  concentration,  and  the  addi- 
tion of  alcoholic  potassium  hydrate,  is  not  affected  by  the 
presence  of  ptomaines.  On  the  other  hand,  the  character- 
istic odor  produced  by  the  action  of  sulphuric  acid  and 
heat  on  atropine  is  scarcely  recognizable  when  ptomaines 
are  present. 

'  In  contradiction  to  this,  see  page  115. 


DELPHININE.  123 

Narceixe.— The  blood-red  color  produced  by  concen- 
trated siilpiiiiric  acid  fails  in  the  presence  of  ptomaines. 

Colchicine — Fuming  nitric  acid  colors  the  ptomaines 
reddish-yellow,  but  the  violet  coloration  of  colchicine  with 
nitric  acid  appears  in  well-defined  form,  even  in  the  pres- 
ence of  ptomaines.  The  other  reactions  for  colchicine  are 
valueless  when  ptomaines  are  present. 

Codeine. — The  blue  coloration  of  codeine  with  concen- 
trated sulpiiuric  acid  holds  good  when  ptomaines  are  present. 
The  same  is  true  of  the  reaction  with  sulphuric  acid,  heat, 
and  the  subsequent  addition  of  nitric  acid.  Fruhde'.s  re- 
agent fails  with  codeine  when  mixed  with  ptomaines,  inas- 
much as  the  bluish  coloration  rapidly  passes  into  a  brown. 

Aconitine. — Phosphoric  acid  and  concentrated  sulphuric 
acid  are  without  reaction  on  the  alkaloid  when  mixed  with 
ptomaines. 

Picrotoxine. — The  reducing  action  of  picrotoxine  on 
alkaline  copper  sulphate  solution  is  seriously  affected  by 
the  presence  of  ptomaines.  The  same  is  true  of  other  tests 
for  this  poison. 

Delphinine. — The  reaction  of  delphinine  with  sul- 
phuric acid  and  bromine  water,  as  well  as  the  one  with 
Frohde's  reagent,  is  so  much  iutlucuced  by  the  presence  of 
ptomaines  that  the  alkaloid  cannot  be  recognized. 

These  results  are  to  be  accepted  with  caution,  as  it  is  not 
reasonable  to  suppose  that  all  ptomaines  will  affect  the  test 
for  the  vegetable  alkaloids  in  the  same  manner,  or  to  the 


124  PTOMAINES. 

same  degree.     Moreover,  there  is  no  proof  that  Tamba 
worked  with  pure  ptomaines. 

Tamba  has  also  proposed  to  separate  vegetable  from 
putrefactive  alkaloids  by  adding  to  ethereal  solutions  of 
mixtures  an  equal  volume  of  a  saturated  ethereal  solution 
of  oxalic  acid,  and  allowing  to  stand,  when  the  oxalates  of 
the  vegetable  alkaloids  will  separate  in  crystalline  form, 
and  the  oxalates  of  the  ptomaines  will  remain  in  solution. 
In  other  words,  the  oxalates  of  the  vegetable  alkaloids 
are  insoluble  in  ether,  while  the  oxalates  of  the  putrefactive 
alkaloids  are  soluble  in  ether.  But,  in  contradiction  to  this, 
BocKLiscH  states  that  the  oxalate  of  cadaverine  is  insoluble 
in  ether. 


CHAPTER    Y. 

METHODS  OF  EXTRACTING  PTOMAINES. 

From  what  has  been  given  in  the  preceding  pages,  one 
may  gather  some  idea  of  the  peculiar  difficulties  with  which 
the  chemist  has  to  contend  in  his  endeavors  to  isolate  the 
basic  products  of  putrefaction.  He  has  to  deal  with  very 
complex  substances,  of  the  nature  and  reactions  of  many 
of  which  he  must  be  ignorant.  Besides,  the  substances 
which  he  seeks  are  often  most  prone  to  undergo  decomposi- 
tion, and  in  this  way  escape  detection.  Many  ptomaines 
are  volatile  or  decomposable  at  any  temperature  near  that 
of  boiling  water.  In  these  cases,  solutions  cannot  be 
evaporated  in  the  ordinary  way  and  the  poison  separated 
from  the  residue.  Indeed,  the  investigator  has  frequently 
been  disappointed  when  on  the  evaporation  of  a  solution, 
which  he  has  demonstrated  to  be  poisonous,  he  finds  that 
the  residue  is  wholly  inert.  Again,  he  may  destroy  the 
ptomaine  by  the  action  of  reagents  which  he  uses.  So 
simple  a  procedure  as  the  removal  of  a  metallic  base  from 
a  solution  containing  a  ptomaine  by  precipitation  with 
hydrogen  sulphide  gas  has  been  known  to  destroy  wholly 
the  ptomaine.  Probably  the  most  perplexing  difficulty  in 
the  isolation  of  these  putrefactive  alkaloids  lies  in  the  great 
number,  complexity,  and  diversity  of  the  other  substances 
present  in  the  decomposing  mass.  The  same  ptomaine  may 
be  present  in  equal  quantities  in  two  samples  of  milk,  and 
yet  it  may  be  easily  obtained  from  the  one,  while  from  the 
other  only  minute  traces  can  be  secured.     The  difference  is 

11* 


126  PTOMAINES. 

due  to  the  fact  that  the  other  constituents  of  the  milk  in 
the  two  samples  are  at  different  stages  of  the  putrefactive 
process,  and,  consequently,  differ  greatly  in  their  reactions 
and  in  their  effects  upon  the  agents  employed  to  isolate 
the  poison.     All  chemists  will  appreciate  these  difficulties. 

One  of  the  first  things  for  the  chemist  who  undertakes 
this  work  to  do,  is  to  ascertain  whether  or  not  his  reagents 
are  pure.  We  have  found  a  number  of  samples  of  German 
ether,  which  was  imported  on  account  of  its  supposed 
purity,  to  yield  on  spontaneous  evaporation  a  residue  which 
gave  several  of  the  alkaloidal  reactions,  and  a  few  drops  of 
which,  injected  under  the  skin  of  a  frog,  caused  paralysis 
and  death  Avithin  a  few  minutes.  We  would  advise  that 
500  c.  cm.  of  the  ether  to  be  used  should  be  allowed  to 
evaporate  spontaneously,  and  its  residue,  if  there  be  one,  be 
examined  both  chemically  and  physiologically.  The  basic 
substance  which  exists  in  some  samples  of  sulphuric  ether 
is  pyridine. 

GuARESCHi  and  Mosso  found  commercial  alcohol  almost 
invariably  to  contain  small  quantities  of  an  alkaloidal  sub- 
stance, the  odor  of  which  is  similar  to  that  of  nicotine  and 
pyridine.  Its  solutions  are  precij^itated  by  gold  chloride, 
phosphowolframic  acid,  phosphomolybdic  acid,  potassium 
iodide,  and  Mayer's  reagent,  but  not  by  jjlatinum  chloride, 
or  tannic  acid.  It  does  not  reduce,  or  reduces  feebly,  ferric 
salts.  From  one  sample  of  alcohol  they  obtained  a  base 
which,  in  addition  to  the  above  reactions,  did  give  a  pre- 
cipitate with  platinum  chloride.  Alcohol  may  be  freed 
from  these  substances  by  distillation  over  tartaric  acid. 

In  amylic  alcohol,  Haitinger  has  found  as  much  as 
0.5  per  cent,  of  pyridine.  It  may  be  purified  in  the  same 
manner  as  recommended  for  ethylic  alcohol. 

Chloroform,  when  found  to  leave  any  residue  on  evapora- 


THE    STAS-OTTO    METHOD.  127 

tion,  should  be  washed  first  witli  distilled  water,  then  with 
distilled  water  rendered  alkaline  with  potassium  carbonate, 
then  dried  over  calcium  chloride  and  distilled. 

Petroleum  ether  sometimes  contains  a  base  which  has  an 
odor  similar  to  trimethylamine  or  pyridine,  and  which  gives 
a  precipitate  with  platinum  chloride  forming  in  octahedra. 

Benzole  may  contain  a  similar  substance. 

The  following  methods  have  been  used  for  the  purpose 
of  extracting  the  putrefactive  alkaloids : 

The  Stas-Otto  Method. — This  method  depends  upon 
the  following  facts:  (1)  the  salts  of  the  alkaloids  are  sol- 
uble in  water  and  alcohol,  and  generally  insoluble  in  ether, 
and  (2)  the  free  alkaloids  are  soluble  in  ether,  and  are  re- 
moved from  alkaline  fluids  by  agitation  with  ether.  These 
principles  are  capable  of  great  variety  in  their  application. 
The  usual  directions  are  as  follows:  Treat  the  mass  under 
examination  with  about  twice  its  weight  of  pure  ninety  per 
cent,  alcohol,  and  from  ten  to  thirty  grains  of  tartaric  or 
oxalic  acid,  digest  the  whole  for  some  time  at  about  70°, 
and  filter.  Evaporate  the  filtrate  at  a  temperature  not  ex- 
ceeding 35°  either  in  a  strong  current  of  air  or  in  vacuo 
over  sulphuric  acid.  Take  up  the  residue  with  absolute 
alcohol,  filter,  and  again  evaporate  at  a  low  temperature. 
Dissolve  this  residue  in  water,  render  alkaline  with  sodium 
bicarbonate,  and  agitate  with  ether.  After  separation  re- 
move the  ether  with  a  pipette,  or  by  means  of  a  separator, 
and  allow  it  to  evaporate  spontaneously.  The  residue  may 
be  further  purified  by  redissolving  in  water  and  again  ex- 
tracting with  ether. 

The  following  modifications  of  this  method  are  em- 
ployed: instead  of  tartaric  or  oxalic  acid,  acetic  acid  is 
frequently  used. 


128  PTOMAINES. 

When  the  fluid  suspected  of  containing  a  ptomaine  is 
already  acid  from  the  development  of  lactic  or  other  organic 
acid,  the  addition  of  an  acid  is  often  dispensed  with. 

Ether  extracts  are  made  from  both  acid  and  alkaline 
solutions. 

Chloroform,  amylic  alcohol,  and  benzene  are  used  as  sol- 
vents after  extraction  with  ether. 

The  modification  of  this  method  as  carried  out  by  Selmi 
and  Marino-Zuco  is  given  in  detail  as  follows : 

The  material  is  divided  as  minutely  as  possible,  placed 
in  a  large  flask  and  treated  with  twice  its  volume  of  90  per 
cent,  alcohol,  and  acidulated  with  tartaric  acid  in  the  pro- 
portion of  0.5  gram  to  100  c.  cm.  of  the  mixture,  taking  care 
from  time  to  time  that  the  reaction  is  permanently  acid. 
The  flask,  which  is  connected  with  a  reflux  condenser,  is 
now  placed  on  the  water-bath  and  kept  at  the  constant 
temperature  of  70°  for  twenty-four  hours.  While  yet 
warm  the  liquid  is  transferred  to  a  special  apparatus  for 
filtration  by  the  aid  of  atmospheric  pressure.  The  liquid 
is  poured  upon  a  wet  cloth  supported  upon  a  perforated 
porcelain  funnel,  which  is  connected  below  with  a  receiver 
exhausted  by  a  water-pump  or  aspirator.  In  this  way 
rapid  filtration  is  secured,  and  by  repeated  washing  the 
extraction  is  made  thorough.  The  acid  alcoholic  liquid  is 
now  transferred  to  a  special  distillation  apparatus. 

A  large  tubulated  retort  of  ten  liters  capacity  is  con- 
nected by  means  of  cork  to  a  large  tubulated  receiver. 
The  tubulure  of  the  retort  is  provided  with  a  small  per- 
forated cork  which  carries  a  glass  tube  finely  drawn  out 
and  extending  to  the  bottom  of  the  retort.  The  tubulure 
of  the  receiver  is  connected  with  Liebig's  bulbs  containing 
dilute  sulphuric  acid  (1  to  10),  and  the  bulbs  in  turn  are 
connected  with  a  water-pump  or  aspirator. 


dragendorff's  method.  129 

In  order  to  prevent  the  passage  of  air  through  the  corks, 
they  are  covered  with  animal  membrane  which  has  been 
freed  from  fat.  By  means  of  the  aspirator  a  fine  current 
of  air  is  drawn  through  the  liquid  and  suffices  to  kec])  it 
constantly  agitated.  The  retort  is  kept  on  the  water-bath 
at  a  temperature  of  from  28°  to  30°.  The  receiver  is  kept 
cold  by  a  current  of  water.  In  this  manner  the  distilla- 
tion of  the  alcohol  goes  on  rapidly  and  conveniently.  More- 
over, decomposition  is  so  far  prevented  that  volatile  bases 
are  never  found  in  the  bulbs. 

The  aqueous  residue,  after  the  removal  of  the  alcohol  by 
distillation,  is  filtered  and  extracted  with  ether  as  long  as 
anything  is  dissolved.  It  is  then  mixed  with  powdered 
•  glass  and  evaporated  to  dryness  in  vacuo.  This  residue  is 
repeatedly  extracted  with  absolute  alcohol.  The  alcohol  is 
distilled  again  in  the  apparatus  already  described.  The 
residue  is  taken  up  with  distilled  water  and  filtered.  It  is 
then  inade  alkaline  with  sodium  bicarbonate  and  repeatedly 
extracted  with  ether,  benzene,  and  chloroform. 

In  order  to  obtain  the  base  from  the  solvent,  the  greater 
part  may  be  evaporated  on  the  water-bath  and  the  re- 
mainder allowed  to  evaporate  spontaneously,  or  the  re- 
mainder may  be  treated  with  dilute  hydrochloric  acid  and 
the  evaporation  continued  on  the  water-bath  or  in  vacuo. 

Dragendorff's  Method.  —  The  finely  divided  sub- 
stance is  digested  for  some  hours  with  water  acidulated 
with  sulphuric  acid  at  from  40°  to  50°.  This  is  repeated 
two  or  three  times  and  the  united,  filtered  extracts  are 
evaporated  to  a  syrup.  This  is  treated  with  four  volumes 
of  alcohol  and  digested  for  twenty-four  hours  at  30°.  After 
cooling  the  alcoholic  extract  is  filtered,  the  residue  washed 
with  70  per  cent,  alcohol,  and  the  united  filtrates  freed 


130  PTOMAINES. 

from  alcohol  bv  distillation.  The  aqueous  residue  diluted 
if  desirable  is  filtered  and  submitted  to  the  following  ex- 
tractions : 

(1)  The  acid  liquid  is  shaken  with  freshly  rectified  petro- 
leum ether  as  long  as  this  reagent  leaves  any  residue  on 
evaporation. 

(2)  The  acid  fluid  is  now  extracted  with  benzene. 

(3)  The  next  solvent  used  is  chloroform. 

(4)  The  liquid  is  now  again  extracted  with  petroleum 
ether  in  order  to  remove  traces  of  benzene  and  chloroform. 

(5)  The  liquid  is  now  made  alkaline  with  ammonia  and 
successively  extracted  with  petroleum  ether,  benzene,  chloro- 
form, and  amylic  alcohol. 

(6)  The  remainder  of  the  ammoniacal  liquid  is  mixed 
with  powdered  glass,  evaporated  to  dryness,  the  residue 
pulverized,  and  extracted  with  chloroform. 

The  residue  obtained  with  each  of  the  above  solvents 
should  be  examined  for  ptomaines. 

Briegee,'s  Method. — The  substance  under  examination 
is  divided  as  finely  as  possible,  and  then  heated  with  water 
slightly  acidified  with  hydrochloric  acid.  During  the 
heating  care  must  be  taken  that  the  feebly  acid  reaction  is 
maintained.  The  heating  should  continue  for  only  a  few 
minutes.  The  liquid  is  then  filtered  and  concentrated  at 
first  on  a  plate  and  then  on  the  water-bath  to  a  syrup.  If 
one  has  material  which  is  highly  odorous,  as  is  the  case 
frequently  both  with  aqueous  and  alcoholic  extracts  of 
putrid  material,  Brieger  recommends  that  a  piece  of 
apparatus  devised  by  Bocklisch  be  used.  The  fluid  to  be 
evaporated  is  placed  in  a  globular  flask,  the  rubber  stopper 
of  which  carries  two  small  glass  tubes.  One  of  these  (b) 
extends  to  the  bottom  of  the  flask,  while  (a)  terminates  just 


BRIEGER  S    METHOD. 


131 


above  the  surface  of  the  liquid.  The  tube  (a)  is  counected 
with  a  water-pump  or  aspirator,  which  draws  tlie  vapor 
through  tlie  tube.  lu  order  to  prevent  the  return  of  con- 
densed fluids,  the  end  of  (a)  in  the  flask  is  curved  upon 
itself.  The  tube  (b)  is  finely  drawn  out  and  through  it  a 
current  of  air  is  constantly  moving.  Tiiis  prevents  the 
formation  of  a  deposit  or  a  pellicle  in  the  fluid.     By  regu- 


lating the  amount  of  air  coming  through  this  tube,  more 
or  less  of  a  vacuum  will  be  formed  in  the  flask.  After 
evaporation  to  a  syrup,  an  extraction  is  made  with  96  per 
cent,  alcohol,  and  the  filtered  extract  is  treated  with  a  warm 
alcoholic  solution  of  lead  acetate.  The  lead  precipitate  is 
removed  by  filtration,  the  filtrate  evaporated  to  a  syrup  and 
again  extracted  with  96  per  cent,  alcohol.  The  alcohol  is 
driven  off;  the  residue  taken  up  with  water;  traces  of 
lead  removed  with  hydrogen  sulphide;  and  the  filtrate, 
acidified  with  hydrochloric  acid,  evaporated  to  a  syrup. 
This  syrup  is  extracted  with  alcohol,  and  the  filtrate  pre- 


132  PTOMAINES. 

cipitated  with  an  alcoholic  solution  of  mercuric  chloride. 
The  mercury  precipitate  is  boiled  with  water,  and  on  ac- 
count of  differences  in  solubility  of  the  double  compounds 
with  mercury,  one  ptomaine  may  be  separated  from  others 
at  this  stage  of  the  process.  (If  thought  best,  the  lead  pre- 
cipitate may  be  freed  from  lead  and  carried  through  the 
following  steps  of  the  process.  Briegee  has  found  small 
amounts  of  ptomaines  in  the  lead  precipitate  only  in  his 
work  with  poisonous  mussels.) 

The  mercury  filtrate  is  freed  from  mercury,  evaporated, 
and  the  excess  of  hydrochloric  acid  carefully  neutralized 
with  soda  (the  reaction  is  kept  feebly  acid),  then  it  is  again 
taken  up  with  alcohol  in  order  to  free  it  from  inorganic 
salts.  The  alcohol  is  evaporated,  the  residue  taken  up  with 
water,  the  remaining  traces  of  hydrochloric  acid  neutralized 
with  soda;  the  whole  acidified  with  nitric  acid,  and 
treated  with  phosphomolybdic  acid.  The  phosphomolyb- 
date  double  compound  is  separated  by  filtration,  and 
decomposed  by  neutral  acetate  of  lead.  This  is  hastened 
by  heating  on  the  water-bath.  The  lead  is  removed  by 
hydrogen  sulphide,  the  filtrate  is  evaporated  to  a  syrup  and 
taken  up  with  alcohol,  from  which  many  ptomaines  are 
deposited  as  chlorides,  or  double  salts  may  be  formed  in  the 
alcoholic  solution.  Brieger  states  that  the  chlorides  as 
deposited  from  the  alcoholic  solution  are  seldom  pure,  and 
he  advises,  for  their  purification,  precipitation  with  gold 
chloride,  platinum  chloride,  or  picric  acid,  and,  on  account 
of  differences  in  solubility  of  these  double  salts,  the  process 
of  purification  is  rendered  more  easy.  The  chloride  of  the 
base  is  obtained  by  removing  the  metallic  base  with 
hydrogen  sulphide;  while  the  picrate  is  taken  up  with 
water,  acidified  with  hydrochloric  acid,  and  repeatedly 
extracted  with  ether,  in  order  to  remove  the  picric  acid. 


THE    METHODS    OF    GAUTIER    AND    ETARD.       133 

The  Methods  of  Gautier  and  Etard. — The  putrid 
matters,  li(i[ui(l  and  solid,  arc  distilled  at  a  low  temperature 
iu  vacuo.  The  distillate  (A)  contains  a  considerable  quan- 
tity of  ammonium  carbonate,  some  phenol,  skatol,  trimethyl- 
amine,  and  the  volatile  fatty  acids.  The  residue  after 
distillation  is  treated  in  succession  by  ether  and  by  alcohol. 

The  extraction  with  ether  (B)  separates  the  ptomaines 
and  some  fatty  acids.  The  alcoholic  extract  (C)  removes  the 
remainder  of  the  fatty  acids,  as  well  as  the  acid  and  neutral 
nitrogeuized  bodies,  almost  all  of  which  are  crystallizable. 
The  insoluble  residue  is  boiled  with  dilute  hydrochloric 
acid,  with  exclusion  of  air,  finally  evaporated  to  dryness, 
and  the  residue  again  extracted  M'ith  alcohol.  This  new 
alcoholic  solution  (D)  can  be  divided  by  acetate  and  sub- 
acetate  of  lead  into  two  principal  portions. 

By  operating  iu  this  manner  the  complex  products  of 
putrefaction  are  readily  separated  into  four  portions. 

In  his  more  recent  work,  Gautier  has  employed  the 
following  method  :  The  putrid  liquids,  after  the  removal  of 
fats,  are  feebly  acidified  \vith  very  dilute  sulphuric  acid, 
then  distilled  in  vacuo  at  a  low  temperature.  The  distillate 
contains  ammonia,  phenol,  iudol,  and  skatol.  The  syrupy 
residue,  separated  from  any  crystals  which  may  have  formed, 
is  rendered  alkaline  with  baryta,  filtered,  and  extracted  a 
great  number  of  times  with  chloroform,  in  order  to  dissolve 
the  bases.  The  solution  is  distilled  at  a  low  temperature, 
either  iu  vacuo  or  iu  a  current  of  carbonic  acid.  The  con- 
tents of  the  retort,  on  being  treated  with  water  and  tartaric 
acid,  separate  into  a  browu  resin  and  a  liquid  portion. 
The  latter  is  removed  and  treated  with  a  dilute  solution  of 
potash,  when  it  gives  oiF  the  odor  of  carbylamine,  which 
was  discovered  by  Gautier  in  18G6,  and  which,  according 
to  Calmel,  is  a  constituent  of  the  venom  of  toads.     The 

1-2 


134  PTOMAINES. 

alkali  also  sets  free  the  bases,  which  are  removed  by  extrac- 
tion with  ether^  and  the  ether  evaporated  in  a  current  of 
carbonic  acid  gas  under  slight  pressure,  then  under  a  bell- 
jar  over  caustic  potash.  The  bases  may  be  separated  by 
fractional  precipitation  with  platinum  chloride,  or,  if  present 
in  sufficient  quantity,  by  distillation  in  vacuo. 

Still  later,  Gautier  has  modified  his  method  as  follows; 
The  alkaline  putrid  liquid  is  treated  with  oxalic  acid  (instead 
of  sulphuric  acid)  to  fi'ee  acidulation  and  as  long  as  the  fatty 
acids  continue  to  separate.  The  liquid  is  then  warmed  and 
distilled  as  long  as  a  turbid  fluid  passes  over.  Pyrrol, 
skatol,  phenol,  indol,  volatile  fatty  acids,  and  some  of  the 
ammonia  pass  over.  The  portion  w'hich  remains  in  the 
retort  is  rendered  alkaline  with  lime  water.  The  precipi- 
tate which  forms,  and  which  contains  the  greater  part  of 
the  fixed  fatty  acids,  is  removed.  The  liquid  portion, 
which  is  alkaline,  is  distilled  to  dryness,  care  being  taken 
to  receive  the  distillate  in  very  dilute  sulphuric  acid.  The 
bases  and  ammonia  pass  over.  The  distillate  is  neutralized 
(with  sulphuric  acid)  and  evaporated  almost  to  dryness, 
then  decanted  from  ammonium  sulphate,  which  crystallizes. 
The  mother-liquor  is  extracted  wdth  concentrated  alcohol, 
which  dissolves  the  sulphates  of  the  ptomaines.  After 
driving  off  the  alcohol,  the  residue  is  rendered  alkaline  with 
caustic  soda,  and  successively  extracted  with  ether,  petro- 
leum ether,  and  chloroform. 

The  lime  precipitate  is  dried  and  extracted  with  ether  of 
thirty-six  degrees,  whicli  removes  any  fixed  bases  that 
may  be  present. 

Remarks  upon  the  Methods. — The  fundamental 
difference  between  the  Stas-Otto  and  the  Deagendorff 
methods  consists  in  the  fact  that  in  the    former  the  first 


REMARKS    UPON    THE     METHODS.  135 

extraction  is  made  with  a  dilute  solution  of"  an  organic  acid 
(tartaric  usually),  while  in  the  second  a  similar  solution  of 
a  mineral  acid  (sulphuric)  is  employed.  In  their  various 
modified  forms  any  solvent  may  be  used  for  separating  the 
alkaloid  from  the  other  constituents  of  the  original  solution. 
Therefore,  the  question  has  been  asked,  Which  is  the  more 
suitable  acid  for  use  in  making  the  first  solution?  The 
answer  to  this  question  will  also  be  the  one  to  the  question, 
Which  is  the  better  method  of  extracting  ptomaines,  the 
Stas-Otto  method  or  that  of  Dragendorff  ?  The  Italian 
chemists  Guareschi  and  Mosso  have  attempted  to  answer 
this  question  experimentally,  and  the  evidence  which  they 
have  furnished  is  condemnatory  of  the  method  of  Dragen- 
dorff. They  show  that  basic  bodies  are  formed  by  the 
action  of  the  dilute  sulphuric  acid  npou  albuminous  sub- 
stances. As  this  point  is  of  vital  importance  to  the  investi- 
gator in  this  branch  of  chemical  science,  we  will  give  a 
brief  abstract  of  the  work  of  Guareschi  and  Mosso : 

One  kilogram  of  fresh  meat  was  treated  with  dilute  sul- 
phuric acid  (in  the  proportion  recommended  in  the  Dra- 
gendorff method)  and  alcohol.  The  dark  solution  after 
filtration  was  made  alkaline  with  ammonium  hydrate  and 
extracted  with  ether.  The  ethereal  solution  gave  on  evap- 
oration an  oily  substance  which  had  the  odor  of  extracts 
obtained  from  putrid  fibrin.  This  substance,  which  was 
obtained  in  considerable  quantity,  was  soluble  in  water  and 
strongly  alkaline  in  reaction.  After  neutralization  with 
hydrochloric  acid,  its  aqueous  solutions  gave  the  following 
alkaloidal  tests : 

(1)  With  platinum  chloride,  a  yellowish-red  precipitate, 
insoluble  in  water,  alcohol,  and  ether,  and  apparently  iden- 
tical with  the  compound  obtained  from  putrid  fibrin  with 
the  same  reagent. 


136  PTOMAINES. 

(2)  With  gold  chloride,  yellow  precipitate,  then  reduc- 
tion to  metallic  gold. 

(3)  With  phosphoraolybdic  acid,  a  heavy,  yellow  precipi- 
tate, forming  a  blue  solution  on  the  addition  of  ammonium 
hydrate, 

(4)  With  phosphotuugstic  acid,  a  white  precipitate. 

(5)  With  Mayer's  reagent,  a  heavy,  whitish  precipi- 
tate. 

(6)  With  picric  acid,  white  precipitate,  instantly. 

(7)  With  iodine  in  potassium  iodide  solution,  a  heavy 
kermes-red  precipitate. 

(8)  With  tannic  acid,  white  precipitate. 

(9)  With  mercuric  chloride,  white,  amorphous  precipi- 
tate. 

(10)  With  Marm:6's  reagent,  heavy  precipitate. 

(11)  With  potassium  ferricyanide,  no  precipitate,  but  a 
cloudiness,  with  the  formation  of  Prussian  blue  on  the  addi- 
tion of  ferric  chloride. 

The  same  quantity  of  this  meat  was  also  treated  by  the 
Stas-Otto  method.  The  alcoholic  extract  was  evaporated 
on  the  water-bath  and  not  in  vacuo.  The  acid  was  neu- 
tralized with  sodium  bicarbonate.  The  ether  extract  gave 
on  evaporation  a  faintly  yellow  residue,  of  not  unpleasant 
odor  and  feebly  alkaline  in  reaction.  After  neutralization 
with  hydrochloric  acid,  it  was  only  slightly  soluble  in 
water.  The  pale  yellow  filtrate  gave  no  precipitate  with 
Nos.  1,  2,  8,  9,  and  10  of  the  above  mentioned  reagents, 
but  gave  a  slight  turbidity  with  Nos.  3,  4,  5,  6,  and  7,  and 
with  11  formed  Prussian  blue. 

GuARESCHi  and  Mosso  conclude  from  this  and  other 
experiments  that  the  Dragendorff  method  is  not  suit- 
able for  the  extraction  of  ptomaines,  and  they  recommend 
the  employment  of  the  Stas-Otto  method  with  these  con- 


REMARKS    UPON    THE    METHODS.  137 

ditious:  (1)  no  more  acid  slioiild  be  added  than  is  abso- 
lutely necessary  to  keej)  the  reaction  acid;  (2)  the  heat  used 
in  evaporation  slionld  not  be  great,  and  it  is  better  that 
evaporation  should  be  made  in  vacuo.  In  this  way,  they 
say,  no  ptomaine  will  be  ol)taiued  from  fresh  tissue. 

The  same  investigators  extracted  fresh  flesh  without  the 
addition  of  any  acid.  Thirty  kilograms  of  perfectly  fresh 
meat  were  digested  for  two  hours  at  from  50°  to  60°  with 
about  oue  and  one-half  volumes  of  water.  The  fluids  of  the 
meat  contained  enough  acid  to  give  to  the  whole  of  this  solu- 
tion an  acid  reaction.  It  was  evaporated  to  half  its  volume 
on  the  water-bath,  filtered,  and  evaporated  still  further. 
The  small  residue  was  taken  up  with  about  four  volumes 
of  96  per  cent,  alcohol.  The  reddish,  alcoholic  solution 
left  on  evaporation  on  the  water-bath  a  brownish  residue, 
which  was  dissolved  in  water  and  extracted  with  ether  (A), 
then  the  solution  was  made  alkaline  with  ammonium 
hydrate  and  again  extracted  with  ether  (B). 

(A)  gave  on  evaporation  and  cooliug  crystals  of  methyl- 
hydautoin,  while  the  mother  liquor  contained  acetic  acid. 

(B)  also  yielded  crystals  of  methyl-hydautoin,  while  the 
mother  liquor  gave  alkaloidal  reactions  with  most  of  the 
general  alkaloidal  reagents,  none  with  platinum  chloride. 
Methyl-hydautoin  does  not  give  these  reactions. 

Marino-Zuco  has  made  many  comparative  tests  with 
these  two  methods.  He  ascertained  that  by  treating  fresh 
eggs,  brain,  liver,  spleen,  kidney,  lungs,  heart,  aud  blood 
by  either  of  the  methods,  he  could  obtain  a  substance  which 
gave  alkaloidal  reactions,  and  which  he  demonstrated  to  be 
choline.  His  experiments  led  him  to  believe  that  choline 
did  not  exist  preformed  in  these  fresh  tissues,  but  that  it 
resulted  from  the  action  of  the  dilute  acids  upon  lecithin. 
It  was  found  most  abundantly  in  those  tissues  which  are 

12* 


138  PTOMAINES. 

rich  in  lecithin,  such  as  the  yolks  of  eggs,  brain,  liver, 
and  blood;  while  only  traces  could  be  obtained  from  the 
whites  of  eggs,  lungs,  and  heart.  The  method  of  Deagen- 
DORFF  was  found  to  furnish  much  larger  quantities  of 
choline  than  could  be  obtained  by  the  Stas-Otto  method. 

Coppola  agrees  with  his  countrymen,  mentioned  above, 
in  condemning  the  method  of  Deagendorff. 

Enough  has  been  said  to  show  that  results  obtained  by 
the  Stas-Otto  method  are  much  more  reliable  than  those 
secured  by  the  method  of  Dragendorff.  However,  the 
former  is  not  a  perfect  method,  nor  has  a  perfect  one  yet 
been  devised.  The  principal  difficulties  met  with  in  the 
Stas-Otto  method  are  as  follows : 

(1)  In  most  instances  the  extraction  of  the  base  is  very 
incomplete.  (2)  The  degree  to  which  the  putrefactive 
alkaloid  is  removed  by  the  solvent  will  depend  very 
largely  upon  the  nature  of  the  other  substances  present. 
This  fact  in  some  cases  aids  and  in  others  hinders  the 
labors  of  the  investigator.  Thus,  several  ptomaines,  which 
when  pure  are  wholly  insoluble  in  ether,  may  be  removed, 
in  part  at  least,  from  organic  mixtures  by  this  solvent  by 
passing  into  the  solution  along  with  other  substances,  but 
if  the  attempt  is  made  to  purify  one  of  these  bases  by  re- 
j)eated  solution  and  extraction  with  ether,  the  result  is  a 
failure,  because  the  more  perfectly  the  alkaloid  is  freed 
from  impurities,  the  less  soluble  it  is  in  ether.  This  criti- 
cism, however,  is  equally  applicable  to  the  Dragendorff 
method,  and  to  all  others  in  so  far  as  extractions  are  made. 

However,  we  may  state  that  whenever  it  is  applicable 
this  method  is  the  best  now  employed.  By  it  the  sub- 
stances are  submitted  to  the  least  chemical  manipulation, 
and  the  results  obtained  are  the  most  reliable.  Many  of 
the  more  complex  putrefactive  products  are  so  easily  de- 


REMARKS    UPON    THE    METHODS.  139 

composed  or  otlierwise  altered  that  tlie  investigator  should 
seek  to  isolate  them  by  the  simplest  methods  possible.  If 
it  can  be  done  without  the  addition  of  any  acid  or  without 
the  application  of  heat,  so  much  the  hotter. 

Especially  is  the  modification  of  tliis  method  employed 
by  Marino-Zuco,  and  already  described,  to  be  commended. 

By  his  method,  Brieger  has  discovered  a  considerable 
number  of  basic  bodies  and  has  given  great  impetus  to  the 
study  of  the  chemistry  of  putrefaction.  The  method  is 
capable  of  a  great  many  modifications.  As  long  ago  as  1868, 
Bergmann  and  Schmiedeberg  employed  precipitation 
with  metallic  salts  in  order  to  obtain  sepsine  from  putrid 
yeast.  The  method  used  by  them  was  as  follows :  Putrid 
yeast  was  diffused  through  parchment  paper;  the  ditfusate 
was  acidified  with  hydrochloric  acid,  and  treated  with  mer- 
curic chloride  solution  until  a  heavy  cloudiness  and,  after 
some  time,  a  slight  precipitate  formed.  This  was  removed 
by  filtration;  the  filtrate  was  rendered  strongly  alkaline 
with  sodium  carbonate,  and  then  further  treated  with  a 
solution  of  mercuric  chloride  as  long  as  a  precipitate 
formed.  This  precipitate  was  collected  on  a  filter,  washed, 
suspended  in  a  little  acidifi-cd  water,  and  decomposed  wnth 
hydrogen  sulphide.  The  precipitate  was  removed,  the  free 
hydrochloric  acid  in  the  filtrate  taken  up  with  silver  car- 
bonate and  the  excess  of  silver  removed  with  hydrogen 
sulphide.  The  filtrate  was  evaporated  to  dryness;  the 
residue  dissolved  in  alcohol  (a  part  remaining  insoluble) 
and  acidified  with  sulphuric  acid,  when  a  colorless,  or 
slightly  yellow  crystalline  precipitate  formed.  The  crys- 
talline sepsine  sulphate  was  purified  by  solution  in  water 
and  precipitation  with  alcohol. 

Brieger  has  obtained  some  of  his  bases  by  a  much  sim- 
plified modification  of  his  complete  method,  which  we  have 


140  PTOMAINES. 

given  in  full.  For  instance,  in  obtaining  neuridine,  he 
treated  the  aqueous  extract  of  the  putrid  material  after 
boiling  and  filtration  with  mercuric  chloride,  collected  the 
precipitate,  decomposed  it  with  hydrogen  sulphide,  evapor- 
ated the  filtrate  on  the  water-bath,  and  extracted  the  base 
from  the  rasidue  with  dilute  alcohol. 

By  this  method  and  its  modifications  Briegee  has 
obtained  many  brilliant  results,  among  which  may  be  men- 
tioned his  discovery  of  mytilotoxine,  typhotoxine,  and 
tetanine.  However,  the  method  is  not  free  from  criticism. 
The  great  number  of  chemical  manipulations  to  which  the 
organic  matter  is  subjected  is  liable  to  lead  to  the  formation 
of  some  basic  substances  and  to  the  destruction  of  others. 
One  is  justified  in  considering  the  isolated  base  as  pre- 
existing in  the  original  material  only  when  it  j)roduces 
symptoms  identical  with  those  caused  by  the  substance  from 
which  it  is  extracted.  There  can  be  no  doubt  that  by  this 
method  many  ptomaines  would  be  decomposed.  With  it 
EhPwENBERG  obtained  from  poisonous  sausage  only  inert 
bases,  and  tyrotoxicon,  the  ptomaine  of  poisonous  cheese, 
is  decomposed  both  by  heat  and  the  hydrogen  sulphide 
emjjloyed.  The  origin  of  the  ptomaines  possessing  a  mus- 
carine-like  action  discovered  by  Bpjeger  has  been  ques- 
tioned by  Gram,  M'ho  states  that  when  the  lactate  of  choline, 
an  inert  substance  which  is  widely  distributed  both  in  plants 
and  animals,  is  heated,  it  is  converted  into  a  poison  with 
such  an  action  (see  page  190). 


CHAPTER    YI. 

CHEMISTRY  OF   THE  TTOMAINES. 

The  basic  substances  described  in  the  following  pages 
are  arranged,  so  far  as  possible,  in  the  regular  natural  order. 
An  inspection  of  the  list  of  these  bases  will  show  the  remark- 
able fact  of  the  predominancy  of  the  amine  type.  Almost 
two-thirds  of  the  known  ptomaines  contain  only  C,  H,  and 
N,  and  represent  simple  ammonia  substitution  compounds. 
Of  the  oxygenated  bases  all  of  those  whose  constitution  is 
known  possess  the  trimethylamiue  molecule  as  their  basic 
constituent,  and  it  is  quite  probable  that  most,  if  not  all,  of 
the  remaining  ptomaines  will  be  found  to  possess  the  same 
or  a  similar  basic  nucleus. 

It  will  be  seen,  furthermore,  that  a  very  large  number  of 
the  ptomaines  described  possess  little  or  no  toxic  action, and 
are,  therefore,  physiologically  inert.  It  would  seem,  as 
Brieger  has  already  pointed  out,  that  a  certain  quantity 
of  oxygen  is  necessary  to  the  formation  of  poisonous  bases. 
A  free  supply  of  oxygen,  on  the  other  hand,  invariably 
yields  non-toxic  ptomaines. 

Methylahine,  CH3.NH2.  —  This  is  the  simplest  or- 
ganic base  that  is  formed  in  the  process  of  putrefaction. 
It  is  ammonia  in  wdiich  one  atom  of  hydrogen  has  been 
replaced  by  the  methyl  radical.  It  occurs  in  herring-brine 
(Tollens,  1866;  Bocklisch,  1885);  in  decomposing  her- 
ring, twelve  days  in  spring  (Bocklisch);  in  pike,  six 
days  in  summer  (Bocklisch)  ;  in  haddock,  two  months  at 


142  PTOMAINES. 

a  low  temperature  (Bocklisch)  ;  in  the  fermentation  of 
choline  chloride  (Hasebroek).  Brieger  has  shown  it  to 
be  present  in  cultures  of  comma  bacillus  on  beef-broth  which 
were  kej)t  for  six  weeks  at  37°-38°.  In  Brieger's 
method,  methylamine  is  found  both  in  the  mercuric  chloride 
precijDitate  and  filtrate.  The  mercury  double  salt  is  readily- 
soluble  in  water,  and  can  thus  be  separated  from  any 
accompanying  cadaverine  or  putresciue.  Methylamine  is 
an  inflammable  gas  of  strong  ammoniacal  odor,  and  burning 
with  a  yellow  flame.  It  is  readily  soluble  in  water,  and  its 
solutions  give  reactions  similar  to  those  of  ammonia.  Its 
salts  are,  as  a  rule,  also  soluble  in  both  water  and  alcohol. 

The  Hydrochloride,  CHg.NHg.HCl,  crystallizes  in 
large  deliquescent  plates.  On  being  heated  with  alkali,  it 
gives  oif  the  odor  of  methylamine. 

The  Platinochloride,  (CH3.NH2.HCl)2PtCl4  (Pt 
=  41.68  per  cent.),  yields  hexagonal  plates  which  usually 
occur  heaped  up  in  several  layers.  It  is  soluble  in  about 
fifty  parts  of  water  at  ordinary  temperature,  and  can  be 
readily  recrystallized  from  hot  water.  It  is  insoluble  in 
absolute  alcohol  and  in  ether. 

The     AUROCHLORIDE,      CH3.NH2.IICI.AUCI3  +  H2O, 

forms  prisms,  which  are  readily  soluble  in  water.  There 
is  also  a  readily  soluble  picrate. 

Methylamine  does  not  possess  any  toxic  action,  even  when 
given  in  fairly  large  doses.  This  physiological  indifference 
is  shared  by  nearly  all  the  monamiues  and  diamines  that 
have  been  obtained  among  the  products  of  putrefaction. 

DiMETHYEAMiNE,  (CIl3)3.NII,  lias  been  found  in  putre- 
fying gelatine,  ten  days  at  35°  (Brieger)  ;  in  yeast  decom- 
posing in  covered  vessels  for  four  weeks  during  summer 
(Brieger)  ;  in  decomposing   perch,   six  days  in  summer 


TRIMETIIYL  AMINE.  143 

(BocKLlscil) ;  uiul  ill  hciTiiig-briiie  (liocKLiSCll).  It  is 
also  formed,  together  with  trimethylaniine,  when  neuridlne 
hydrochloride  is  distilled  with  sodium  hydrate  (Briegek, 
I.,  28).  It  occurs  in  the  mercuric  chloride  precipitate  as 
well  as  filtrate.  From  cadaveriue  it  can  be  separated  by 
platinum  chloride,  since  cadaverine  platinochloride  is  diffi- 
cultly soluble  in  cold  water,  and  recrystallizes  from  hot 
water,  whereas  the  dimethylamine  double  salt  remains  in 
the  mother  liquor.  In  like  manner  it  can  be  separated 
from  neuridlne.  From  choline  it  can  be  isolated  by  recrys- 
tallizing  the  mercuric  chloride  precipitate  from  hot  water. 

The  free  base  is  a  gas  at  ordinary  temperature,  but  can 
be  condensed  to  a  liquid  which  boils  at  8°-9°.  The 
hydrochloride,  (CH3)2.NH.HCL,  crystallizes  in  needles, 
which  deliquesce  on  exposure  to  air  and  are  soluble  in 
absolute  alcohol  (Brieger,  I.,  56).  It  is  insoluble  in 
absolute  alcohol  (Bockliscii)  but  soluble  in  chloroform 
(Behrend),  and  can  then  be  separated  from  methylainine 
hydrochloride,  which  is  insoluble  in  chloroform. 

The  Platinochloride,  [(CH3),.NH.HCl]2PtCl„  (Pt 
=  39.36  per  cent.),  crystallizes  in  long  needles,  which 
are  easily  soluble  in  hot  water,  less  soluble  in  cold  water. 
Sometimes  it  forms  orange-yellow  plates  or  prisms,  or  else 
small  needles. 

The  Aurochloride,  (CH3)2.NH.HCl.AuCl3,  forms 
needles  (Bocklisgh)  which  are  insoluble  in  absolute 
alcohol,  or  large  yellow  monoclinic  plates  (Hjortdahl). 

Trimethylamine,  (CH3)3N,  has  been  for  a  long  time 
known  to  occur  in  animal  and  vegetable  tissues. 
Dessaignes  showed  its  presence  in  leaves  of  Chenopodium 
(1851),  in  the  blood  of  calves  (1857),  and  later  in  human 
urine.     It  has  been  obtained  from  ergot  (Secale  cornutum) 


144  PTOMAINES. 

by  Walz  (1852)  and  Briegee  (1886);  from  herring-brine 
by  Wertheim,  AVinkles,  Tollexs,  and  Bocklisch, 
and  from  cultures  of  the  comma  bacillus  by  Brieger. 
In  these  substances,  with  the  exception  of  herring-brine,  it 
probably  does  not  exist  preformed,  but  is  rather  a  product 
of  the  method  employed  for  its  isolation.  In  fact,  Brieger 
has  shown  that  it  does  not  exist  in  ergot,  but  is  formed  at 
the  expense  of  the  choline  present,  which,  on  distillation 
with  potash,  decomjDoses  and  yields  trimethylamine.  It 
may  have  a  similar  origin  in  most  of  the  other  cases,  since 
choline  is  now  known  to  be  widely  disseminated  in  plants 
and  animals,  either  as  such  or  as  a  constituent  of  the  more 
complex  lecithin.  Trimethylamine  has  been  found  in  the 
putrefaction  of  yeast  (Hesse,  1857;  Muller,  1858);  in 
cheese  after  six  Aveeks  in  midsummer  (Brieger)  ;  iu 
human  liver  and  spleen  after  from  two  to  seven  days 
(Brieger)  ;  in  perch  after  six  days  in  midsummer  (Bock- 
lisch) ;  in  mussel  (Mytilus  edulis)  after  sixteen  days 
(Brieger)  ;  in  putrefying  brains  after  from  one  to  two 
months,  and  in  fresh  brains  (Guareschi  and  Mosso) ;  and 
in  cultures  of  tlie  Streptococcus  pyogenes  on  beef-broth, 
bouillon,  meat  extract,  and  blood-serum  (Brieger).  It  is 
also  formed  when  choline,  betaine,  or  neuridine  is  distilled 
with  potash. 

Trimethylamine  is  found  both  in  the  mercuric  chloride 
precipitate  and  filtrate.  It  remains  in  the  mother  liquor 
from  which  cadaverine,  neuridine,  and  dimethylamine 
platinochlorides  have  crystallized.  If  an  aqueous  solution 
of  mercuric  chloride  is  used  as  the  precipitant,  the  tri- 
methylamine will  be  found  almost  entirely  in  the  filtrate, 
from  which  it  can  be  obtained  after  removal  of  the 
mercury  by  evaporating  the  filtrate  to  dryness,  extracting 


ETHYLAMINE.  145 

with  alcohol  and  treating  the  solution  thus  obtained  with 
alcoholic  platinum  chloride. 

The  free  base  is  a  liquid  possessing  a  strong,  fish-like 
odor.  Its  boiling  point  is  9.3°.  It  is  strongly  alkaline  in 
reaction  and  freely  soluble  in  water. 

The  Hydrochloride,  (CH3)3N.HC1,  is  deliquescent 
and  freely  soluble  in  water  and  alcohol.  Heated  to  285° 
it  decomposes.  With  alkalies  it  gives  off  the  odor  of  the 
free  base. 

The  Platinochloride,  [(CH3)3N.HCl],PtCl,  (Pt  = 
37.25  per  cent.),  is  soluble  in  hot  water,  from  which, 
on  cooling,  it  recrystallizes  in  orange-red  octahedra  or 
needles,  which  do  not  lose  water  wheu  heated  at  100°-110° 
(Bocklisch). 

The  Aurochloride,  (CH3)3N.HCl.AuCl3  (Au  =  49.37 
per  cent.),  is  easily  soluble,  and  hence  can  be  separated 
from  choline  aurochloride,  which  is  difficultly  soluble. 
Similarly,  this  base  can  be  separated  from  ammonia  by  the 
use  of  gold  chloride. 

Trimethylamine  is  not  a  strong  poison,  since  very  large 
doses  of  it  must  be  given  iu  order  to  bring  out  any  physio- 
logical disturbances. 

Ethylamixe,  C2H5.NH2,  is  formed  in  putrefying  yeast 
(Hes.se,  1857);  iu  wheat  flour  (Sullivan,  1858);  and 
also  in  the  distillation  of  beet-sugar  residues. 

It  is  a  strongly  ammoniacal  liquid  boiling  at  18.7°,  and 
is  miscible  with  water  iu  every  proportion.  Like  the  other 
amines,  it  is  combustible.  It  possesses  strong  basic  proper- 
ties, and  is  capable  of  expelling  ammonia  from  its  salts  iu  a 
mauner  analogous  to  the  action  of  the  fixed  alkalies. 

The   Hydrochloride,    C2H5.NH2.HCI,    forms    deli- 

13 


146  PTOMAINES. 

quescent  plates,  which  melt  at  76°-80°.  It  is  readily 
soluble  in  water  and  alcohol. 

The  Platixochloride,  [CJIyl^I{2.}IC\\FtC\^,  forms 
orange-yellow  rhombohedra  (Weltzien),  or  hexagonal- 
rhombohedral  crystals  (Topsoe). 

The  AuEOCHLOEiDE,  CjHj.jN'Hg.HCl.AuClg,  forms  gold- 
yellow  mouocliuic  prisms,  readily  soluble  in  water. 

With  picric  acid  it  forms  short  brown  prisms,  not  very 
soluble  in  water. 

DiETHYLAMiNE,  (C2H5)2NH,  has  been  obtained  by 
BoCKLLSCH  from  pike  which  were  allowed  to  putrefy  for 
six  days  in  summer. 

It  is  an  inflammable  liquid  which  boils  at  57.5°,  pos- 
sesses strong  basic  properties,  and  is  soluble  in  water. 

The  Hydrochloride,  (C2Hg)2]SrH.HCl,  crystallizes  in 
needles  (Bocklisch);  in  long  needles  and  prisms  from  ab- 
solute alcohol ;  in  plates  from  ether-alcohol.  These  are 
not  deliquescent  and  are  easily  soluble  in  water  and  in 
chloroform;  rather  difficultly  in  absolute  alcohol.  Heated 
with  sodium  hydrate  it  gives  off  alkaline  vapors.  From  an 
alcoholic  solution  it  is  precipitated  by  addition  of  alcoholic 
mercuric  chloride.  The  mercury  double  salt  is  difficultly 
soluble  in  hot  water,  from  which  it  recrystallizes  on  cooling. 

The  Platixochloride,  [(C2H5)2.NH.HCl]2PtCl„  crys- 
tallizes in  orange-yellow  monocliuic  crystals,  which  are 
easily  soluble  in  water. 

The  AuROCHLORiDE,  (C2H5)2.NH.HCl.AuCl3  (Au  = 
47.69  per  cent),  forms  trimetric  crystals  (TOPSOEJ,  which 
are  difficultly  soluble  (Booklisch).    It  melts  at  about  165°. 

With  picric  acid  it  forms  an  easily  soluble  picrate  (Lea). 

Triethylamine,  CgHjjN  =  (C2H5)3N,  was  obtained  by 
Brieger  from  haddock  which  were  exposed  for  five  days 


ISO- AMYLAMINE.  147 

iu  an  open  vessel  during  siininier.  He  obtained  it  by  dis- 
tilling with  potash,  after  removal  of  platinum  by  hydrogen 
sulphide,  the  mother  liquor  from  which  neuridine,  the  base 
C2H>jN2,  muscarine,  and  gadinine  had  successively  crystal- 
lized (see  page  204). 

The  free  base  is  oily  in  character  and  possesses  an  ani- 
moniacal  odor.  It  is  but  slightly  soluble  in  water,  and 
boils  at  89°-89.5°. 

The  PLATrNOCHLORIDE,  [(C2H5)3N.HCl]2PtCl,  (Pt= 
32  20  per  cent.),  crystallizes  in  needles  which  are  readily 
soluble  in  water. 

With  mercuric  chloride  the  aqueous  solution  gives  no 
precipitate. 

With  picric  acid  it  yields  yellow  needles  which  are  but 
slightly  soluble  iu  cold  water. 

Propylamine,  C3H7.NH2,  is  isomeric  with  trimethyla- 
miue  and  can,  therefore,  be  easily  confounded  with  that 
base.  There  are  two  propylamines  possil)le  represented  by 
the  formula  CHg.CH^.CH^.NH^  and  (CPy^.CH.NH^. 
The  former,  or  the  normal  compound,  boils  at  47°-48°, 
whilst  the  latter,  or  iso-propylamine,  boils  at  31.5°.  Both 
are  liquids  possessing  an  ammoniacal  fish-like  odor.  They 
form  crystalline  salts  ;  the  hydrochlorides  melt  respectively 
at  155°'- 158°,  and  at  139.5°. 

Iso-propylamine  (?)  has  been  found  among  the  distilla- 
tion products  of  the  vinasse  of  beet-root  molasses.  Propy- 
lamine has  been  obtained  by  Brieger  from  cultures  of  the 
bacteria  of  human  fteces  on  gelatine.  Schavanert  has  iso- 
lated from  the  organs  of  a  cadaver  a  basic  substance  which 
was  said  to  possess  an  odor  similar  to  propylamine. 

Iso-amylamine,  C^HijN  =  (CH3)2.CH.CH2.CH2.NH2, 
has  been  obtained  by  Limpricht  in  the  distillation  of  horn 


148  PTOMAINES. 

with  potash;  it  also  occurs  in  the  putrefaction  of  yeast 
(MtJLLEE,  Hesse,  1857).     It  boils  at  95°. 

Capeoylamine  (Hexylamine),  CgHigN,  has  been 
found  by  Hesse  (1857)  to  occur  in  the  putrefaction  of 
yeast.  Hager  isolated  from  some  putrid  material  what 
he  thought  to  be  a  mixture  of  amylamine  and  caproyla- 
mine,  and  named  it  septicine. 

.  Tetanotoxine,  CgHjjN,  (?)  was  obtained  by  BEiEaER 
(1887)  as  one  of  the  products  of  the  growth  of  the  tetanus 
microbe  on  beef- broth  or  on  brain-broth.  It  is  tetanizing 
in  its  action,  produces  first  tremor,  then  paralysis  and  vio- 
lent convulsions. 

Spasmotoxine,  a  base  as  yet  of  unknown  composition, 
produces  in  animals  violent  clonic  and  tonic  convulsions. 
It  was  obtained  by  Brieger  (1887)  from  cultures  of  the 
tetanus  germ  on  beef-broth. 

Another  toxine  was  obtained  in  cultures  of  the  tetanus 
microbe  which  produced  a  complete  tetanus,  salivation, 
and  tear  secretion.  Besides  these  three  bases  he  isolated 
another  toxic  substance,  tetanine  (page  211). 

A  Base,  CgH^^lSr,  isomeric,  but  not  identical,  with  alde- 
hyde-collidine,  was  obtained  by  JSTencki  as  early  as  1876; 
by  allowing  a  mixture  of  200  grams  of  pancreas  and  600 
grams  of  gelatine  in  ten  litres  of  water  to  putrefy  for  five 
days  at  40°.  The  method  used  by  Nencki  for  its  isola- 
tion is  as  follows :  The  fluid  mass  was  distilled  with  sul- 
phuric acid,  to  drive  off  the  volatile  acids,  then  rendered 
alkaline  with  barium  hydrate,  and  again  distilled.  The 
distillate  was  received  in  dilute  hydrochloric  acid,  and  on 


A     BASE,    CgHiiN.  149 

evaporation  gave  a  crystalline  residue  of  ammonium  chlo- 
ride, and  of  a  salt  which  formed  in  long  rhombic  plates. 
The  latter  were  separated  from  the  ammonium  salt  by 
absolute  alcohol.  The  free  base  was  obtained  from  the 
salt  by  treating  it  with  sodium  hydrate,  and  extracting  the 
solution  with  ether. 

The  free  base  is  oily  in  character,  and  possesses  a  pecu- 
liar, not  unpleasant  odor.  It  readily  absorbs  carbonic  acid 
g-as  from  the  air,  formino;  after  a  time  a  lamellar,  crystal- 
line  mass  of  the  carbonate.  The  salt  of  this  base  on  heating 
gives  off  an  oil  which  burns  with  a  smoky  flame,  and  pos- 
sesses an  odor  similar  to  that  of  xylol  or  cumol.  Nencki 
is,  therefore,  of  the  opinion  that  the  ptomaine  is  an  aro- 
matic base,  probably  an  isopheuyl-ethylamine  of  the  fol- 
lowing composition  :    CgHg  —  CH    ^TT.    He  thinks  that 

it  may  arise  from  the  putrefaction  of  tyrosin,  according  to 
the  following  equation  : 

CgH^^NOg  =  C3H11N  +  CO,  +  O. 

We  know  that  tyrosin  does  split  up,  on  being  heated  to 
270°,  into  carbonic  acid  and  oxyphenyl-ethylamine,  thus  : 

CsH<C|.CH.NH,COOH  =  C^H./^H^g^^g^^CO, 

In  1883  Erlenmeyer  and  Lipp  observed  that  pheuyl- 
rt-amidopropionic  acid  (phenyl-alanine),  on  dry  distilla- 
tion, decomposed  with  the  formation,  among  other  pro- 
ducts, of  a  base  having  the  composition  CgHj^N.  This 
base  was  found  to  be  identical  with  phenyl-ethylamiue, 
CgH5.CH2.CH2.NH2,  and  in  its  properties  it  resembles 
Nencki's  base,  which  is  isomeric  with  it.  From  the  fact 
that  phenyl-a-amidopropionic  acid  is  a  well-known  putre- 

13* 


150  PTOMAINES. 

factive  product,  it  would  seem  that  Nencki's  base  may 
arise  either  from  the  putrefactive  decomposition  of  the 
acid,  or  from  the  splitting  up  of  the  acid  as  a  consequence 
of  the  method  employed  in  isolating  the  base.  The  latter 
would  seem  to  be  the  most  probable  explanation  of  the 
genesis  of  this  base,  inasmuch  as  Beiegee,  by  using  his 
method  for  the  isolation  of  ptomaines,  has  not  been  able  to 
obtain  it  from  putrid  gelatine. 

The  Platinochloride,  (C8Hi,N.HCl)2PtCl,  (Pt  = 
30.16  per  cent.),  is  readily  soluble  in  hot  water,  and  but 
slightly  soluble  in  cold  water,  and  can  be,  therefore,  recrys- 
tallized  from  water.     It  forms  beautiful,  flat  needles. 

Nencki  also  obtained  from  putrid  gelatine,  under  certain 
ill-defined  conditions,  especially  when  no  glycocoll  was 
present,  a  basic  product  which  gave,  with  sulphuric  acid, 
large  lamellar  crystals.  The  free  base  forms  a  thick  color- 
less syrup,  possessing  a  nauseous,  bitter  taste.  It  did  not 
become  crystalline  even  after  standing  some  time.  Unlike 
the  base  CgHj^N,  it  is  not  volatile,  and  is,  therefore,  ob- 
tained on  evaporation  of  the  acidulated  solution  after  pre- 
vious removal  of  the  volatile  bases  by  distillation  with 
baryta. 

A  Base,  CgHjgN,  was  obtained  by  Gautier  and  Etard 
from  the  chloroformic  extracts  (see  method,  page  133)  from 
putrefying  mackerel,  as  well  as  from  the  decomposing  flesh 
of  the  horse  and  ox.  It  is  regarded  by  these  authors  as  a 
constant  and  definite  product  of  the  bacterial  fermentation 
of  albuminoid  substances  ;  but  this  view  is  hardly  justifi- 
able, inasmuch  as  the  base  has  not  been  found  by  other 
investigators.  Nencki  (1882)  asserted  the  identity  of  this 
base  with  the  one  which  he  had  isolated  in   1876,  and  to 


A     RASE,    C„H,.,N.  151 


i:{ 


which  he  had  ascribed  the  formida  CgTTj,N.  On  the  otlier 
hand  Gautier  and  Etard  consider  their  base  to  be  iden- 
tical with  the  liydro(X)llidine  obtained  by  Caiiours  and 
Etard  by  the  action  of  seleuinni  on  nicotine. 

The  free  base  is  an  alkaline,  almost  colorless,  oily  liquid, 
possessinj^  a  penetrating  odor  resembling  that  of  seringa. 
It  is  volatile  without  decomposition  and  boils  at  about  205°, 
whilst  hydroeollidine  boils  at  210°.  Its  density  at  zero  is 
1.0296.  When  exposed  to  the  air  it  oxidizes  slowly,  be- 
comes brown  and  vis(;ous,  and  at  the  same  time  absorbs 
carbonic  acid.  It  differs  from  a  collidine  in  possessing  a 
strong  reducing  action,  since  both  the  gold  and  ])latinum 
double  salts  become  reduced  on  heating. 

The  Hydrochloride,  CgHigN.HCl,  is  very  soluble  in 
water  and  in  alcohol,  and  usually  forms  fine  needles  re- 
sembling snow  crystals.  It  is  neutral  in  reaction  and  pos- 
sesses a  bitter  taste.  In  the  presence  of  an  excess  of  acid 
it  reddens  and  resinifies. 

The  Platinochloride,  (C8Hi3N.HCl)2PtCl,  (Pt  = 
29.7  per  cent.),  is  of  a  light  yellow,  flesh  color,  crystalline, 
and  but  slightly  soluble.  It  dissolves  on  warming  and  re- 
crystallizes  in  bent  needles. 

The  AuROCHLORiDE  is  rather  soluble,  and  becomes 
slowly  reduced  in  the  cold  ;  rapidly  on  warming. 

Physiological,  Action. — This  isomer  of  hydroeolli- 
dine is  strongly  poisonous.  Even  so  small  a  dose  as  0.0017 
gram  of  the  hydrochloride  produced,  when  injected  under 
the  skin  of  a  bird,  marked  unsteadiness  of  gait  followed  by 
paralysis  of  the  extremities,  and  finally  death.  The  pupils 
are  normal  and  the  heart  stops  in  diastole.  Larger  doses 
(0.007  gram)  cause  at  first  vomiting  and  staggering,  which 
soon  give  way  to  a  condition  of  exaltation.     Toward  the 


152  PTOMAINES. 

end  tetanic  convulsions  set  in,  followed  by  almost  complete 
paralysis. 

A  Base,  CgHjgN,  isomeric  with  parvoliue,  has  been  ex- 
tracted by  Gautier  and  Etard  (1881)  from  decomposing 
mackerel  and  horseflesh.  The  method  employed  by  these 
chemists  for  its  isolation  is  given  on  page  134.  The  iden- 
tity of  this  base  with  the  synthetic  parvoline,  obtained  by 
Waage  by  heating  ammonia  with  propionic  aldehyde  in  a 
sealed  tube  at  200°,  cannot  be  considered  to  be  definitely 
settled,  although  an  apj)arent  identity  exists  in  regard  to 
their  boiling  points.  Thus,  the  synthetic  parvoline  boils  at 
193°-196°,  whilst  Gautier  and  Etard  assign  to  their 
base  a  boiling  point  a  little  below  200°.  Further  investi- 
gation is  necessary  to  decide  upon  the  question  of  the  iden- 
tity of  this  base  with  parvoline,  or  of  the  ptomaine  CgH^gN 
with  hydrocollidine. 

The  free  base  is  an  oily,  amber-colored  liquid,  possessing 
the  odor  of  hawthorn  blossoms.  It  is  slightly  soluble  in 
water  ;  very  soluble  in  alcohol,  in  ether,  and  in  chloroform. 
Its  boiling  point,  as  stated  above,  is  a  trifle  below  200°. 
Like  the  bases  CgH^gN  and  CmlligN  it  becomes  brown  and 
soon  resinifies  on  exposure  to  air. 

The  Platinochloride,  (CgHigN.HCOaPtCl,  (Pt  = 
28.5  per  cent.),  is  slightly  soluble,  crystalline,  and  flesh 
colored ;  exposed  to  the  air  it  soon  becomes  pink. 

The  AuROCHLORiDE  is  quite  soluble. 

A  Base,  CjoHi^N,  was  isolated  by  Guareschi  and 
Mosso  (1883)  from  ox-blood  fibrin  which  had  been  allowed 
to  putrefy  for  five  months.  In  1886  Oechsner  de 
CoxiNCK  found  it  among  the  basic  products  formed  in  the 
putrefaction  of  the  jelly-fish  (poulpes  marins,  Hugounenq, 


A    BASE,    CioHj.,N.  153 

page  21).  The  method  used  for  its  extraction  was  that  of 
Gautier  and  Etard  (see  page  133).  It  forms  a  brownish 
oil  of  strong  alkaline  reaction,  which  soon  resinifies.  It 
possesses  a  weak  pyridine  or  coniine  odor,  and  is  but 
slightly  soluble  in  water. 

In  regard  to  the  constitution  of  this  ptomaine  we  know 
nothing,  but  from  its  physical  characters  it  would  seem  to 
possess  a  pyridine  nucleus.  It  is  isomeric  with  corindine, 
a  homologue  of  parvoline,  and  collidine,  which  has  been  ob- 
tained from  coal  tar. 

For  the  behavior  of  the  hydrochloride  to  alkaloidal  re- 
agents, see  Table  I. 

The  Hydrochloride,  CmlljjN.HCl,  crystallizes  in 
colorless  cholesterine-like  plates  which  are  somewhat  deli- 
quescent. 

The  Platinochloride,  (CioHi5N.HCl)2PtCl,  (Pt  = 
27.49  per  cent.),  forms  a  light  flesh-colored,  crystalline  pre- 
cipitate, and  is  insoluble  in  water,  alcohol,  and  ether.  It 
does  not  resinify  and  is  stable  at  100°. 

In  its  physiological  action  this  ptomaine  resembles 
curara,  although  it  is  by  no  means  as  strong.  0.012  gram 
of  the  free  base  produced  in  a  frog  dilatation  of  the  pupil, 
and  slowing  of  the  respiration.  The  nostrils  were  motion- 
less, and  within  five  honrs  complete  paralysis  of  the  mus- 
cles took  place.  The  reflex  excitability  gradually  dimin- 
ished until  it  finally  disappeared.  An  orange-blossom  odor 
was  observed  about  the  frogs  which  were  poisoned  by 
this  ptomaine.  The  same  amount  of  ptomaine  injected 
into  a  green  finch  produced  vomiting,  and  a  condition 
of  weakness  and  decreased  sensibility,  followed  soon, 
however,  by  recovery.  A  rat  was  not  affected  by  0.020 
gram  of  the  free  base.  The  hydrochloride  acts  much  more 
energetically. 


15-i  PTOMAINES. 

Ethylidenediamine  (■?),  CgHgNa- — This  base  was 
considered  at  first  by  Brieger  to  be  identical  ^vith  ethy- 
lenediamine,  but  subsequent  comparison  showed  this  to  be 
an  error.  Tlius,  the  former  is  poisonous  and  does  not  form 
a  gold  salt,  whilst  the  latter  is  not  poisonous  and  does  form 
a  rather  difficultly  soluble  gold  salt.  Again,  ethylene- 
diamine  forms  a  platinochloride  which  is  almost  insoluble 
in  hot  water,  whereas  the  platinum  double  salt  of  the 
ptomaine  is  much  more  easily  soluble.  Brieger  is,  there- 
fore, inclined  to  think  that  it  is  identical  with  ethylidene- 
diamine,  CH3.CH(NH2)2,  rather  than  with  ethylenediamine, 
which  has  this  structure,  CH2.NH2.CH2.ISrH2.  This 
ptomaine  was  obtained  by  Brieger  (I.,  44)  from  decom- 
posing haddock  (see  page  204). 

The  free  base  can  be  obtained,  without  decomposition,  on 
distilling  the  hydrochloride  with  sodium  hydrate. 

The  Hydrochloride,  C2H8N2.2HCI,  crystallizes  in 
long  glistening  needles  which  are  readily  soluble  iu  water, 
insoluble  in  absolute  alcohol.  It  gives  no  combination 
with  gold  chloride.  For  its  behavior  to  alkaloidal  reagents 
see  Table  I. 

The  Platinochloride,  C2H,X2.2HCl.PtCl4  (Pt.  = 
41.85  per  cent.),  forms  small  yellow  plates  which  are 
moderately  difficultly  soluble  in  water.  It  can  be  readily 
recrystallized  from  hot  water. 

Physiological  Action. — Frogs  seem  to  be  less  sus- 
ceptible to  the  action  of  this  poison  than  mice  or  guinea-pigs. 
In  the  latter,  it  produces  a  short  time  after  injection  an 
abundant  periodic  flow  of  secretion  from  the  nose,  mouth, 
and  eyes.  The  pupils  dilate  and  the  eyeballs  project. 
Violent  dyspnoea  then  comes  on  and  predominates  until  the 
death  of  the  animal,  which  does  not  take  place  for  twenty- 
four  hours  or  more.     The  heart  is  stopped  in  diastole. 


TRIMETHYLENEDI  AMINE.  155 

Trimethylexediamine  (■?),  CgHgNg,  is  a  toxic  base 
isolated  by  Beieger  (1887)  from  cultures  of  the  comma 
bacillus  on  beef-broth.  It  is  present,  however,  in  exceed- 
ingly minute  quantity  and  occurs  in  the  mercuric  chloride 
precipitate,  from  which  it  is  obtained  by  the  following 
method  :  The  precipitate  is  decomposed  by  hydrogen  sul- 
phide, the  filtrate  evaporated  to  dryness,  and  the  residue 
taken  up  with  absolute  alcohol  and  precipitated  by  an 
alcoholic  solution  of  sodium  picrate.  The  precipitate 
thus  obtained  consists  of  the  picrates  of  cadaverine,  creati- 
nine, and  of  this  new  base.  It  is  boiled  with  absolute 
alcohol  to  remove  the  insoluble  cadaverine  picrate;  the 
filtrate  is  evaporated  to  expel  the  alcohol,  and  the  bases 
then  converted  into  the  platinum  double  salts,  whereby  the 
easily  soluble  creatinine  platiuochloride  can  be  separated 
from  the  corresponding  less  soluble  compound  of  the  new 
base. 

Owing  to  the  small  quantity  of  this  substance  present,  a 
complete  study  of  its  properties  has  not  as  yet  been  made. 
It  gives  difficultly  soluble  precipitates  with  gold  chloride 
and  with  platinum  chloride;  the  compound  with  the  latter 
crystallizes  in  long  needles.  With  picric  acid  it  gives  a 
precipitate  consisting  of  felted  needles  which  resemble 
creatinine  picrate;  they  melt  at  198°.  Phosphomolybdic 
acid  yields  a  precipitate  crystallizing  in  plates,  whilst  potas- 
sium-bismuth iodide  gives  dark  colored  fine  needles.  From 
its  physiological  action  its  seems  to  be  identical  with  the 
basic  substance  isolated  from  choleraic  bodies  by  different 
observers.  It  causes  violent  convulsions  and  muscle 
tremor. 

Besides  trimethylenediamine,  another  toxine  was  obtained 
by  Brieger  from  cholera  cultures,  but  in  quantity  insuffi- 
cient for  analysis.      It  was  obtained    from   the  mercuric 


156  PTOMAINES. 

chloride  filtrate  after  elimination  of  methylamine,  trimethy- 
lamine,  and  traces  of  choline  and  creatinine,  as  an  insoluble 
platinum  double  salt.  Subcutaneous  injection  of  this  base 
into  mice  produced  a  paralysis-like  lethargic  condition, 
slowing  of  respiration  and  heart's  action,  lowering  of 
temperature,  and  finally,  death  in  twelve  to  twenty -four 
hours.     In  some  cases  bloody  stools  were  passed. 

PuTEESCiXE,  CJH^2^2}  i'^  ^  diamine  which  almost  in- 
variably occurs  together  with  cadaverine,  with  which  it  is 
apparently  closely  related.  This  base  was  also  discovered 
by  Briegee  (II.,  42),  who  has  obtained  it  from  putrefying 
human  internal  organs  (for  four  months  at  a  low  tempera- 
ture without  access  of  much  oxygen)  ;  and  from  the  same 
material,  decomposing  at  the  ordinary  temperature  of  the 
room,  for  from  three  days  to  three  weeks.  It  has  also  been 
obtained  from  herring,  twelve  days  in  spring ;  from  pike, 
six  days  in  summer  ;  from  haddock,  two  months  (BoCK- 
eisch).  Also  from  putrid  mussel,  sixteen  days  (Brieger)  ; 
and  from  human  as  well  as  horse  flesh.  Brieger  has 
obtained  it  from  cultures  of  the  bacteria  of  human  faeces  on 
gelatine,  and  in  small  quantity  in  rather  old  cultures  of 
the  comma  bacillus  on  beef-broth ;  in  larger  quantity  in 
cultures  of  the  same  germ  on  blood  serum. 

Although  putrescine  is  recognizable  on  about  the  fourth 
day  of  the  putrefaction,  yet  it  does  not  occur  in  appreciable 
quantity  until  about  the  eleventh  day.  The  amount  that 
is  formed  increases  as  the  putrefaction  goes  on,  so  that  a 
considerable  quantity  may  be  obtained  after  two  or  three 
weeks.  A  very  good  source  for  the  preparation  of  putrescine, 
cadaverine,  and  neuridine  is  gelatine  which  has  been  allowed 
to  decompose  in  contact  with  water  for  some  weeks. 
Keuridiue  is,  apparently,  formed  first^  but  is  soon  replaced 


PUTRESCINE.  157 

by  the  former  two  bases.  In  the  process  of  extraction  it 
is  first  obtained  in  the  alcoholic  mercuric  chloride  precipi- 
tate. For  its  separation  from  cadaveriue  and  other 
accompanying  bases,  see  page  169. 

Putrescine  (from  putresco,  to  rot,  to  putrefy)  is  a  water- 
clear,  rather  thin  liquid  of  a  peculiar  semen-Hke  odor, 
reminding  one  somewhat  of  the  pyridine  bases.  It  absorbs 
carbonic  acid  encrgeticallv  from  the  air,  without  losinu- 
thereby  the  repulsive  odor.  The  boiling  point  of  the  free 
base,  as  ordinarily  obtained,  is  about  135°.  It  is  not 
decomposed  by  distillation  with  potassium  hydrate,  and  is 
rather  difficultly  volatile  with  steam.  With  acids  it  forms 
beautiful  crystalline  salts.  Putrescine  unites  with  water, 
like  ethylenediamine,  to  form  a  hydrate,  and  this  water  can 
only  be  removed  by  distillation  with  metallic  sodium.  The 
perfectly  anhydrous  base  boils  at  156°-157°,  and  then 
solidifies  to  plates.  Like  cadaverine,  it  is  difficultly  soluble 
in  ether. 

The  constitution  of  putrescine  has  not  been  determined. 
From  its  empirical  composition  and  its  apparent  relation 
to  cadaveriue  (peutamethylenediamine)  it  might  be  sup- 
posed to  be  a  butylenediamine  (probably  tetramethylene- 
diamiue).  However,  on  heating  the  concentrated  aqueous 
solution  of  the  hydrochloride  with  potassium  nitrite  there 
is  23roduced  an  oil,  soluble  in  water,  from  which  it  can  be 
extracted  with  ether.  This  oil,  on  treatment  with  phenol 
and  sulphuric  acid,  gives  Liebermann's  nitroso-reaction, 
showing  conclusively  that  putrescine  is  not  a  primary 
diamine  (butylenediamine),  but  is  rather  a  secondary 
diamine  (Brieger,  II.,  42),  Again,  if  it  is  a  primary 
diamine  it  should  take  up,  on  repeated  treatment  with 
methyl  iodide,  six  methyl  radicals ;  whereas,  if  it  is  a 
secondary  diamine,  only  four  methyl   radicals  can  enter  the 

14 


158  PTOMAINES. 

molecule.  Thus  to  illustrate,  methylamiue,  CHg.NHg  (a 
primary  amine),  combines  with  three  molecules  of  methyl 
iodide  to  form  (CH3)^N.HI.  Similarly,  dimethylamine, 
(CH3)2.NH,  requires  only  two  molecules  to  form  (CH3)4N.HI. 
In  the  case  of  diamines,  double  this  number  of  methyl  groups 
is  required  to  effect  complete  saturation.  As  a  matter  of 
fact,  Bkieger  (III.,  101),  on  treating  putrescine  with  methyl 
iodide,  has  succeeded  in  introducing  four,  and  only  four 
methyl  radicals,  and  hence  it  follows  that  putrescine  is  not 
a  primary  amine,  but  is  a  secondary  amine. 

Putrescine,  therefore,  is  not  a  butylenediamine,  nor  is  it 
a  homologue  of  cadaverine.  From  these  facts  it  follows 
that  putrescine  possesses  one  of  the  subjoined  formulae. 

It  is  either  dimethyl-ethylenediamime : 

CH2— NH— CH3 
CH2— NH— CH3 

or,  it  is  methyl-ethyl-methylenediamine  : 

2\  TT 

\CH3. 

The  tetra-methyl  substitution-product  of  putrescine  can 
be  distilled  without  decomposition.  The  free  base  crystal- 
lizes in  long  prisms.  The  hydrochloride  forms  small 
needles  which  are  easily  soluble;  with  phosphotungstic  acid 
it  gives  a  white  crystalline  precipitate,  with  phospho- 
molybdic  acid  a  yellow  crystalline  precipitate,  with  picric 
acid  needles.  Potassium-bismuth  iodide  gives  a  brownish- 
red  amorphous  deposit,  whilst  the  potassium  mercuric 
iodide  forms  prisms.     Gold  chloride  yields  difficultly,  and 


PUTRESCINK.  159 

plntinuin  chloride  easily  .soluble  octaliedni ;  aqueous  mer- 
curic chloride  forms  needles. 

The  aurochloride  has  the  formula  CJi^i^^-'^AnC]^. 

This  tetra-methyl  derivative  of  putrescine  is  enormously 
poisonous  as  compared  with  putrescine.  The  symptoms 
are  the  same  as  those  produced  by  muscarine  or  neurine. 
They  are  :  abundant  salivation,  dyspnoea ;  res])iration  at 
first  increases,  then  decreases;  contraction  of  the  pupils; 
paralysis  of  the  mus(;les  of  the  limbs  and  trunk,  increased 
peristaltic  action  of  the  intestines,  ejaculation  of  semen, 
dribbling  of  urine,  and,  finally,  violent  clonic  convulsions. 
Ill  the  case  of  mice  and  guinea-pigs,  the  convulsions  are 
prominent  immediately  after  the  injection  of  the  poison. 

Putrescine  Hydrochloride,  CJH12N2.2HCI,  forms 
long  colorless  needles,  which  are  very  easily  soluble  in 
water;  difficultly  so  in  dilute  alcohol ;  entirely  insoluble  in 
absolute  alcohol,  and  can  thus  be  separated  from  cadave- 
rine  hydrochloride.  To  accomplish  this  separation  it  is, 
])erhaps,  better  to  dissolve  the  mixture  of  the  hydrochlo- 
rides in  hot  96  per  cent,  alcohol.  On  cooling  the  solution 
thus  obtained  the  putrescine  salt  crystallizes  out,  whereas 
that  of  cadaverine  remains  in  solution.  Putrescine  hydro- 
chloride differs  from  cadaverine  hydrochloride,  in  that  it  is 
not  hygroscopic,  and  can  be  exposed  for  days  to  the  air 
without  suffering  any  change  on  the  surface  of  the  crystals. 

For  the  behavior  of  the  free  base  and  the  hydrochloride 
to  alkaloidal  reagents,  see  Table  I.  Putrescine  is  not 
toxic,  though  it  possesses  some  marked  physiological 
properties  (see  Cadaverine,  page  163).  It  is  optically 
inactive. 

The  Platinochloride,  C,Hi2N2.2HCl.PtCl,  (Pt  = 
39.52  per  cent.),  often  appears  under  the  microscojie  in  the 
form  of  cholesterine-like  plates.     In  the  pure  condition  it 


160  PTOMAINES. 

appears  as  six-sided  plates,  which  are  superposed  in  layers. 
The  crystals  possess  a  splendid  silvery  lustre,  and  are  rather 
difficultly  soluble  in  cold  water ;  less  so  in  hot  water. 

The  AuROCHLORiDE,  C4H12N2.2HCI.2AUCI3  +  2H2O, 
crystallizes  likewise  in  plates,  which  are  difficultly  soluble 
in  cold  water.  It  can,  therefore,  be  readily  separated  from 
cadaverine  aurochloride,  which  is  easily  soluble  iu  water. 
The  water  of  crystallization  can  be  driven  off  completely 
only  at  110°  (Brieger).  According  to  Bocklisch,  it 
loses  this  water  on  standing  over  sulphuric  acid,  or  on 
heating  at  100°. 

The  PiCRATE,  C4Hi2N2.2C6H2(N02)30H,  is  difficultly 
soluble,  and  crystallizes  from  a  hot  aqueous  solution  in 
needles ;  from  hot  aqueous  alcohol  on  cooling  in  yellow 
plates.  It  begins  to  brown  at  230°,  and  on  further  heating 
becomes  darker,  till  finally,  at  250°,  it  decomposes  with 
rapid  evolution  of  gas  (Bocklisch). 

The  Carbonate  is  crystalline. 

The  Mercury  double  salt  is  easily  soluble  in  a  large 
quantity  of  water,  and  can  thus  be  separated  from  the 
cadaverine  salt,  which  is  difficultly  soluble.  From  hot 
concentrated  aqueous  solution  it  crystallizes  in  needles. 

Cadaverine,  CgHj^Ng,  is  a  diamine  isomeric  with  neu- 
ridine,  and,  like  the  latter,  it  occurs  very  frequently  iu 
decomposing  animal  tissues.  It  is  a  very  striking  fact,  that 
in  ordinary  putrefaction  as  choline  disappears  the  diamines 
appear  and  increase  iu  quantity  according  as  the  time  of 
putrefaction  is  extended.  It  has  been  obtained  by  Brieger 
from  human  lungs,  hearts,  livers,  etc.  (hence  the  name), 
which  were  allowed  to  putrefy  at  the  ordinary  temperature 
for  three  days ;  from  the  same  organs,  and  from  horseflesh, 
after   four  months  iu  a  closed  vessel  at  —  9°  to  +  5°  : 


CADAVERINE.  IGl 

IVoiu  putrid  mussel  after  sixteen  days;  and  it  seems  to  be 
a  constant  product  of  the  jirowth  of  the  comma  bacillus, 
irrespective  of  the  soil  on  which  it  is  cultivated. 

BocKLiscH  has  isolated  it  from  perch  and  pike,  six  days 
in  midsummer;  from  herrin^j;,  twelve  days  in  spring; 
from  haddock,  two  months  at  a  low  temperature ;  from 
cultivations  of  Finkler  and  Prior's  vibrio  proteus  on 
beef-broth,  thirty  to  thirty-five  days  at  37°  to  38°  (Ber. 
20,  1441).  Cadaverine  seems  to  be  a  constant  product  of 
the  activity  of  the  genus  vibrio,  inasmuch  as  it  does  not 
occur  in  cultures  in  which  this  germ  is  absent.  Thus,  it  is 
not  present  in  the  excrements  of  healthy  or  typhoid  patients ; 
in  cultures  of  Emmerich's  bacillus,  typhus  bacillus,  and  of 
the  micrococci  of  pus.  Oechsner  de  Coxinck  has  found 
it  in  putrid  jelly-fish  (Hogounenq,  page  23).  Cadaverine 
occurs  in  the  mercuric  chloride  precipitate,  from  which  it  is 
isolated  according  to  the  methods  given  on  pages  155  and  169. 

This  base  was  at  first  ascribed  the  formula  CgHigNg?  but 
subsequent  researches  led  Brieger  and  Bocklisch  to  the 
adoption  of  the  formula  C5HijX2.  In  1883,  Ladenburg 
prepared,  as  the  first  step  in  the  synthesis  of  piperidiue,  a 
base,  pentamethylenediamine,  possessing  the  same  empirical 
formula  as  cadaverine,  and  later  (Ber.  18,  2956)  he  showed 
the  possibility  of  the  identity  of  these  two  bases.  This  led 
to  their  direct  comparison  and  the  successful  establishment 
of  their  identity.  In  fact,  Ladexburg,  as  a  crucial  test  of 
the  identity,  converted  cadaverine  into  piperidiue,  and 
found  the  latter  base  to  agree  entirely  in  its  chemical  and 
physical  properties  with  those  of  the  natural  alkaloid  [Ber. 
19,  2586).  Ladexburg,  however,  observed  one  apparent 
difference  between  cadaverine  and  pentamethylenediamine, 
and  that  was  in  the  composition  of  the  mercury  double  salts. 
That  of  the  former  base,  whether  obtained  from  alcoholic 

14* 


162  PTOMAINES. 

or  aqueous  solution  (Bocklisch,  Ber.  20,  1441),  was  found 
to  combine  with  four  molecules  of  mercuric  chloride ; 
whereas  the  double  salt  of  pentamethylenediamine  was  found 
bj  Ladexburg  to  contain  only  three  molecules  of  mer- 
curic chloride.  Subsequently  he  found  that  he  had  pre- 
pared this  salt  by  mixing  the  aqueous  solutions  of  the 
hydrochloride  of  the  base  and  of  the  mercuric  chloride  in 
the  molecular  ratio  of  1  to  4,  and  on  using  a  larger  excess 
of  mercuric  chloride  he  obtained  a  salt  containing  four 
molecules  of  mercuric  chloride  (5er.  20,  2216).  The  com- 
plete identity  of  these  two  bases  has,  therefore,  been  estab- 
lished. The  constitutional  formula  of  cadaverine  is,  there- 
fore : 

NH2  —  CH2  —  CH2  —  CH2  —  CH3 — CH2 — NH^. 

Cadaverine  forms  a  somewhat  thick,  water-clear,  syrupy 
liquid,  which  possesses  an  exceedingly  unpleasant  odor, 
resembling  somewhat  that  of  coniine  (piperidiue)  and  of 
semen.  When  dehydrated  with  potassium  hydrate  it  boils 
at  115°-120^  (Brieger).  It  boils  at  175°  (Brieger, 
III.,  98),  and  fumes  in  the  air.  The  base  eagerly  absorbs 
carbonic  acid  from  the  air,  and  solidifies  into  a  crystalline 
mass.  It  is  volatile  with  steam,  and  can  be  distilled,  with- 
out decomposition,  even  in  presence  of  sodium  or  barium 
hydrate,  or  soda  lime.  Neuridine,  its  isomer,  decomposes 
under  these  circumstances.  When  heated  with  alcoholic 
potash  and  chloroform  it  does  not  give  the  iso-nitril  reac- 
tion, nor  does  it  give  the  characteristic  odor  of  oil  of  mus- 
tard on  treatment  with  carbon  disulphide  and  mercuric 
chloride.  These  two  reactions  are  given  by  primary  mon- 
amines,  but  in  this  case  they  are  not  given  by  cadaverine, 
a  primary  diamine.  It  is  probable  that  this  behavior  holds 
true  for  all  diamines. 


CADAVERINE.  163 

Cadaverine  is,  undoubtedly,  identical  with  the  so-called 
"animal  coniine,"  which  has  been  isolated  at  various  times 
from  cadavers. 

Cadaverine  and  putrescine  were  at  first  regarded  as 
physiologically  indifferent,  but  more  recent  investigations 
by  ScHEURLEX,  Grawitz,  and  others,  show  that  both  these 
bases  are  capable  of  producing  strong  inflammation  and 
necrosis.  In  cholera  Asiatica  tlie  necrosis  of  the  intestinal 
epithelium  is  quite  common,  and  it  would  seem  that  this 
pathological  change  is  due  to  the  presence  of  these  bases. 
Besides  these  local  effects,  they  prevent,  even  in  small  quan- 
tity, the  coagulation  of  blood,  and  render  it  "  laky."  Ac- 
cording to  Grawitz,  cadaverine  seems  to  hinder  the  growth 
of  bacteria.     Both  bases  are  also  optically  inactive. 

When  cadaverine  is  treated  with  methyl  iodide,  there  is 
obtained  a  base,  the  hydrochloride  of  which  gives  with 
platinum  chloride  a  double  salt,  having  the  composition  : 
C5H,2(CH3)2N2.2HCl.PtCl,.  This  new  base,  therefore,  is 
cadaverine,  in  which  two  atoms  of  hydrogen  have  been 
replaced  by  two  methyl  radicals.  The  platiuochloride  of 
this  derivative  forms  long,  clear  red  needles,  which,  unlike 
those  of  cadaverine,  do  not  change  their  shape  on  repeated 
recrystallization.  It  is  moderately  difficultly  soluble  in 
water  (Brieger,  II.,  41).  Since  cadaverine  is  a  primary 
diamine  it  should  combine  with  six  molecules  of  methyl 
iodide  to  form  a  saturated  compound.  This,  however,  has 
not  been  obtained. 

The  Hydrochloride,  C5Hi^N2.2HC1,  crystallizes  in 
beautiful,  long  deliquescent  needles  (Brieger).  Accord- 
ing to  BoCKLisCH,  it  forms  long  colorless  needles  or  prisms  ; 
crystallizes  from  alcohol  in  plates  and  is  not  deliquescent. 
It  is  soluble  in  water,  alcohol,  alcohol-ether;  but  is  insoluble 
in  absolute  alcohol,  ether,  etc.     It  can  readily  be  separated 


164  PTOMAINES. 

from  putrescine  hydrochloride  by  its  solubility  in  96  per 
cent,  alcohol  (Bocklisch).  The  strictly  pure  base,  as  well 
as  the  hydrochloride,  does  not  give  a  blue  color  with  ferric 
chloride  and  potassium  ferricyanide.  For  reactions  of  the 
hydrochloride  and  of  the  free  base,  see  Table  I. 

Cadaverine  hydrochloride  on  dry  distillation  decomposes 
into  NHg,  HCl,  and  piperidine,  C^H^jIS^.  The  latter  is  a 
well-known  poisonous  alkaloid  which  exists  in  the  combined 
state  in  black  pepper.  It  is  not  known  whether  this  change, 
whereby  the  non-poisonous  cadaverine  is  converted  into  a 
toxic  base,  can  take  place  under  the  influence  of  bacteria 
during  the  processes  of  putrefaction  or  not.  However,  it 
does  not  seem  improbable  that  this  simple  chemical  change 
should  be  effected  through  the  action  of  living  organisms ; 
for  Schmidt  has  already  shown  that  the  almost  physiologi- 
cally indifferent  choline,  when  subjected  to  the  action  of 
the  bacteria  of  hay-infusion,  decomposes  into  a  neurine-like 
base  possessing  a  muscariue-like  action,  and  under  certain 
conditions  it  yields  a  base  which  in  its  action  resembles 
pilocarpine. 

The  Sulphate  likcAvise  forms  beautiful,  well-formed 
needles,  and  in  its  solubility  corresponds  to  the  hydro- 
chloride. 

The  Platinochloride,  C^Hi.N^.SHCl.PtCl,  (Pt  = 
38.49  per  cent.),  crystallizes  after  some  time,  on  the  addition 
of  platinum  chloride  to  a  not  too  concentrated  solution  of  the 
hydrochloride,  in  the  form  of  long,  beautiful  orange-red 
needles  (Bocklisch).  Ordinarily  it  is  obtained  at  first  in 
long,  dirty  red  needles,  which  on  repeated  recrystallization 
become  clearer,  and  assume  a  form  similar  to  that  of  ammo- 
nium platinochloride.  It  forms  chrome -yellow  rhombic 
prisms  which  are  short  and  octahedra-like.  In  polarized 
light  they  are  strongly  double  refracting.    It  is  very  slightly 


CADAVERINE,  165 

soluble  in  cold  water;  can  be  recrystallized  from  hot  water 
(Bocklisch). 

The  AuROCHLORiDE,C,Hi,N2.2HC1.2AuCl3(Au  =  50.25 
per  cent.),  crystallizes  partly  in  cubes,  and  partly  in  long 
needles  which  at  first  possess  a  bright  lustre,  but  under  the 
desiccator  soon  effloresce  and  become  opacpie.  The  water 
of  crystallization  is  completely  removed  on  standing  over 
sulphuric  acid.  It  is  very  easily  soluble,  and  melts  at  188° 
(Bocklisch). 

The  PiCRATE,  C5Hi,X2-2C6H,(XO2)30H,  forms  yellow 
plates  which  are  difficultly  soluble  in  cold  water.  From 
hot  water  it  crystallizes  in  long  prisms,  which  melt  at  221° 
with  decomposition.  It  is  insoluble  in  absolute  alcohol 
and  can  be  recrystallized  from  hot  dilute  alcohol. 

Cadaverine  hydrochloride  combines  with  mercuric  chlo- 
ride, when  the  aqueous  solutions  of  these  two  salts  are 
mixed  in  the  molecular  ratio  of  1  to  4,  to  form  CgHj^Nj. 
2HC1.3Ho;C],.  This  salt  can  be  recrvstallized  from  hot 
water  (Ladexburg).  When  an  excess  of  mercuric  chlo- 
ride is  used  the  double  salt  has  the  composition  CgHj^Ng. 
2HC1.4HgCl2.  This  last  salt  melts  at  216°  (Ladenburg)  ; 
at  211°  (Bocklisch).  It  is  difficultly  soluble  in  cold 
water ;  from  hot  water  it  crystallizes  in  needles  or  plates 
(Bocklisch). 

The  Neutral  Oxalate,  C5Hi,N2.H2aO,+  SH^O,  was 
prepared  by  Bocklisch  by  adding  a  little  less  than  the  cal- 
culated quantity  of  alcoholic  oxalic  acid  to  the  cadaverine. 
The  precipitate  may  be  recrystallized  from  liot  dilute  alco- 
hol, when  it  is  obtained  in  the  form  of  needles,  which  melt 
at  about  160°  and  at  the  same  time  give  oiFgas. 

The  Acid  Oxalate,  CJiy,^.,.2}rl.,Cfi,  +  U^0,  is  made 
by  bringing  the  neutral  salt  into  alcoholic  oxalic  acid.  It 
is  soluble  in  hot  dilute  alcohol,  and  recrystallizes  from  it  in 


166  PTOMAINES. 

quadratic  plates,  sometimes  in  glistening  needles.  It  melts 
at  143°  with  decomposition.  After  it  has  been  dried 
over  sulphuric  acid,  it  loses  on  being  heated  to  105°-110° 
one  molecule  of  water  (Bocklisch,  Ber.  20,  1441).  The 
insolubility  of  these  oxalates  in  absolute  alcohol  shows  the 
fallacy  of  Tamba's  distinction  between  ptomaines  and  vege- 
table alkaloids.     (See  page  124.) 

Neuridine,  CgHj^Ng,  was  the  first  diamine  isolated  from 
animal  tissues  (Brieger,  1884).  It  is  one  of  the  most 
common  products  of  putrefaction,  and  as  such  has  been 
obtained  by  Brieger  from  putrid  horseflesh,  beef,  human 
muscle,  five  to  six  days ;  from  haddock,  five  days  in  sum- 
mer; from  cheese,  six  weeks  in  summer;  from  gelatine, 
ten  days  at  35° ;  from  decomposing  human  internal  organs, 
three  to  eleven  days. 

Bocklisch  has  obtained  it  from  perch,  six  days  in 
summer;  from  barbel  after  three  days  in  summer. 

It  has  also  been  obtained  from  fresh  eggs  in  the  prepa- 
ration of  choline  by  heating  with  baryta ;  and  also  from 
fresh  brain  by  heating  with  two  per  cent,  hydrochloric  acid 
(Brieger,  I.,  57-61). 

Neuridine  is  almost  invariably  accompanied  by  choline, 
and  as  the  duration  of  putrefaction  increases,  the  latter 
gradually  decreases  in  amount  and  yields  a  corresponding 
increase  in  trimethylamine,  whereas,  the  yield  of  neuridine 
increases  from  day  to  day.  The  amount  of  neuridine 
formed  depends  upon  the  nature  of  the  organ  employed  in 
putrefaction.  The  greatest  yield  is  obtained  from  gelatin- 
ous tissues,  such  as  intestines;  and  especially  from  pure 
gelatine.  On  the  other  hand,  such  tissues  as  the  spleen 
and  liver  yield  but  little. 

Neuridine  comes  down  in  the  mercuric  chloride  precipi- 


NEURIDINE.  167 

tate  (sonietimes  it  occurs  in  the  Hltrate),  and  can  then  be  iso- 
hited  iVoni  the  other  bases  present  in  a  number  of  ways.  One 
method  is  given  on  page  205.  Another  convenient  method 
of  separation  is  to  precipitate  it  from  alcoholic  solution  by 
alcoholic  picric  acid.  The  picrate  thus  obtained  is,  for  the 
purpose  of  fnrtlier  purification,  recrystallized  from  absolute 
alcohol,  then  decomposed  by  extracting  its  acid  solution 
with  ether  (to  remove  the  picric  acid)  and  evaporating  the 
aqueous  solution  to  dryness.  The  residue  is  now  extracted 
with  alcohol  and  the  alcoholic  solution  precipitated  by 
alcoholic  platinum  chloride.  The  platinochloride  can  now 
be  recrystallized  from  hot  water. 

The  free  base,  as  obtained  by  the  treatment  of  the 
hydrochloride  with  moist  freshly  preci})itatod  silver  oxide, 
possesses  an  extremely  repulsive  odor,  similar  to  that  of 
human  semen.  On  evaporation  of  its  aqueous  solution  it 
yields  a  gelatinous-like  mass,  and  at  the  same  time  slowly 
decomposes.  It  does  not  crystallize  when  evaporated  in  a 
vacuum,  and  decomposes  even  under  these  conditions.  The 
same  disagreeable  odor  is  obtained  when  the  hydrochloride 
is  warmed  with  potassium  hydrate.  Beieger  (I.,  24) 
regards  this  decomposition-product  of  neuridine  as  an 
oxidation-product  of  the  original  substance. 

The  free  base  is  very  readily  soluble  in  water,  but  is 
insoluble  in  erher  and  absolute  alcohol  ;  diificultly  soluble 
in  amyl  alcohol.  It  gives  white  precipitates  with  mercuric 
chloride,  neutral  and  basic  lead  acetates.  When  distilled 
with  fixed  alkali  it  yields  di-  and  tri-methylamine,  thus 
probably  showing  some  relation  to  neurine,  hence  the  name 
neuridine.  It  does  not  give  Hoffmann's  iso-nitril  reaction, 
but  it  does  not  follow  from  this,  as  shown  under  cadaverine, 
that  it  may  not  be  a  primary  diamine.  It  is  isomeric  with 
cadaverine. 


168  PTOMAINES. 

The  Hydrochloride,  C5H14N2.2HCI,  crystallizes  in 
long  needles  which  are  extremely  soluble  in  water  and 
in  dilute  alcohol,  but  are  insoluble  in  absolute  alcohol, 
ether,  benzole,  chloroform,  petroleum  ether,  benzene,  amyl 
alcohol,  etc.  Its  insolubility  in  absolute  alcohol  may  be 
used  to  eflfect  a  separation  from  choline  hydrochloride.  It 
can  be  recrystallized  from  slightly  warm  dilute  alcohol. 
Although  the  pure  salt  is  insoluble  in  the  reagents  just 
given,  nevertheless,  in  the  presence  of  other  animal  matter 
it  is  dissolved  in  greater  or  less  quantity,  and  hence  can  be 
ol>tained  by  the  Stas-Otto  as  well  as  by  the  Dragen- 
DOREF  method.  The  crystals  resemble  urea  in  form.  On 
heating  very  cautiously  the  salt  sublimes,  and  at  the  same 
time  appears  to  undergo  a  partial  internal  decomposition, 
inasmuch  as  many  of  the  groups  of  needles  in  the  sublimate 
are  colored  red  or  blue.  For  the  behavior  of  the  hydro- 
chloride with  the  alkaloidal  reagents,  see  Table  I. 

Pure  neuridine  is  not  poisonous,  but  as  long  as  it  is 
contaminated  with  other  putrefaction  products  it  possesses  a 
toxic  action  similar  to  that  of  peptotoxine.  This  holds 
true  for  the  other  non-poisonous  bases. 

The  PLATmocHLORiDE,  CJI,,N^.2BC].FtC\,  (Pt= 
38.49  per  cent.),  crystallizes  in  beautiful  flat  needles.  Re- 
crystallized  from  hot  water,  it  forms  aggregations  of  small, 
clear,  yellow  needles.  It  is  readily  soluble  in  water,  from 
which  it  is  precipitated  on  the  addition  of  alcohol. 

The  AuROCHLORiDE,  C5H14N2.2HCI.2AUCI3  (Au= 
50.38  per  cent.),  is  fairly  difficultly  soluble  in  cold  water 
(Bocklisch),  and  crystallizes  on  cooling  of  the  hot,  satu- 
rated solution  in  bunches  of  clear,  yellow,  short  needles. 

The  PiCRATE,  C5Hi4N2.2CgH2(N'02)30H,  can  be  recrys- 
tallized from  boiling  water,  in  which  it  is  very  difficultly 
soluble,  in  the  form  of  needles  united  in  plumose  groups. 
It  is  almost  insoluble  in  cold  water ;  less  difficultly  soluble 


SAPRINE.  169 

in  alcohol.  It  is  not  fusible,  but  begins  to  brown  and  give 
off  yellow  vapors  at  230°,  and  carbonizes  completely  at 
250°. 

Saprine,  CjHjgNj,  was  found  in  human  livers  and 
spleens  after  three  weeks'  putrefaction  (Brieger,  II.,  30, 
46,  58).  It  occurs  together  with  cadaverine,  putrescine 
and  mydaleine  in  the  mercuric  chloride  precipitate.  To 
separate  these  bases,  Brieger  used  the  following  process : 
The  mercury  salts  were  decomposed  with  hydrogen  sul- 
phide, the  filtrate  evaporated  to  dryness,  and  the  residue 
then  extracted  with  alcohol.  The  putrescine  hydrochloride 
is  insoluble  in  alcohol,  and  is  thus  removed.  The  alcoholic 
solution  was  treated  wdth  platinum  chloride,  which  precipi- 
tated the  greater  part  of  the  cadaverine.  The  mother 
liquor,  on  concentration,  yielded  a  mixture  of  the  platino- 
chlorides  of  cadaverine  and  saprine.  Each  successive  crop 
contained  more  of  the  saprine  double  salt.  The  two  kinds 
of  crystals  were  now  separated  by  means  of  a  magnifying 
glass.  The  saprine  platinochloride  thus  obtained  was  finally 
purified  by  repeated  recrystallization  from  water.  The 
mother  liquor,  after  the  removal  of  the  saprine  platino- 
chloride, contains  the  mydaleine  salt,  which,  on  account  of 
its  solubility  in  water,  crystallizes  only  on  concentration,  or 
on  standing  under  a  desiccator.  The  mercuric  chloride 
filtrate  contains  some  mydaleine  and  the  ptomaine  which 
yields  a  platinochloride  containing  28.40  per  cent,  platinum. 

The  free  base  is  a  diamine.  It  possesses  a  weak  pyridine- 
like  odor,  and  can  be  distilled  with  steam  or  with  potas- 
sium hydrate  without  undergoing  decomposition.  In  its 
reactions  it  behaves  the  same  as  cadaverine,  except  that  it 
gives  an  amorphous  precipitate  with  potassium-bismuth 
iodide,  whereas  cadaverine  gives  a  crystalline  -precipitate. 

15 


170  PTOMAINES. 

The  free  base  gives  an  immediate  intense  blue  color  with 
ferric  chloride  and  potassium  ferricyanide. 

The  Hydrochloride,  C5HjgN2.2HCl,  forms  flat  needles 
which  are  not  hygroscopic  (distinction  from  cadaverine 
hydrochloride).  Its  reactions  are  the  same  as  those  of 
cadaverine  hydrochloride  (see  Table  I.).  It  is,  however, 
tinged  slightly  blue  by  a  mixture  of  ferric  chloride  and 
potassium  ferricyanide,  whereas  the  free  base  gives  an 
intense  blue.  It  differs  from  cadaverine  in  that  it  does  not 
give  the  reddish-brown  color  with  potassium  bichromate 
and  sulphuric  acid.  Again,  it  forms  no  aurochloride ; 
while,  on  the  other  hand,  cadaverine  hydrochloride  yields 
an  easily  soluble  salt,  crystallizing  in  splendid  needles. 

The  Platinochloride,  C5lIjgN2.2IICl.PtCl4,  forms 
parallel,  aggregated,  pointed  crystals,  which  are  somewhat 
soluble  in  water,  and  are  thus  distinguished  from  cadaverine 
platinochloride,  which  crystallizes  in  rhombs,  and  is  diffi- 
cultly soluble  in  water.  Saprine  does  not  form  an  auro- 
chloride.    Physiologically,  it  is  indifferent. 

A  Base,  C7lIj(,N2. — Until  very  recently  the  nature  of  the 
basic  substances  which  are  formed  as  products  of  the  alco- 
holic fermentation  of  sugar  or  molasses  has  been  but  little 
understood.  Kramer  and  Pinner,  in  1869,  found  in  crude 
fusel  oil  a  small  quantity  of  a  volatile  base  which  they 
apparently  identified  with  a  collidine.  This  observation  was 
confirmed  by  Ordonneau,  and  others ;  and  still  more  re- 
cently (January,  1888)  Morin  has  contributed  an  elaborate 
paper  upon  the  bases  formed  during  alcoholic  fermentation. 
The  portion  of  crude  fusel  oil  which  boils  above  130.5° 
was  extracted  with  slightly  acidulated  water,  the  acid 
aqueous  solution  thus  obtained  was  made  alkaline,  and  the 
oily  bases  which  were  thus  set  free  were  then  distilled  with 


A    BASE,    C^HjqNo.  171 

vapor  of  water.  Tlie  free  bases  were  dried  over  potassium 
hydrate  and  then  subjected  to  fractional  distillation.  Three 
fractions  were  thus  obtained,  boiling  respectively  at  155°- 
160°,  171°-172°,  and  185°-190°.  Only  the  second  frac- 
tion, which  boils  at  171°-172°,  was  studied  and  was  found 
to  possess  the  formula  C^HjoIS^g'  Heated  with  concentrated 
hydrochloric  acid,  it  is  decomposed  in  part  with  the  forma- 
tion of  ammonia.  It  combines  with  ethyl  iodide  to  form  a 
yellow,  crystalline  compound,  which  is  soluble  in  water 
and  alcohol,  insoluble  in  ether.  The  hydrochloride  crys- 
tallizes in  fine  white  needles,  soluble  in  water  and  alcohol, 
and  but  very  slightly  soluble  in  absolute  ether.  The  free 
base,  as  stated  above,  boils  at  171°-172°,  is  very  soluble  in 
water,  alcohol,  ether,  etc.  When  pure  it  forms  a  colorless, 
strongly  refracting,  very  mobile  oil,  which  possesses  a  char- 
acteristic nauseating  odor,  but  slightly  resembling  that  of 
the  pyridine  bases.  Its  density  at  12°  is  0.9826  ;  toward 
litmus  paper  the  base  shows  no  decided  reaction.  The 
platinochloride  is  crystalline  and  is  very  soluble  in  water 
and  alcohol,  slightly  soluble  in  ether.  Potassio-mercuric 
iodide  does  not  precipitate  the  aqueous  solution  of  the  free 
base,  but  in  solutions  of  the  hydrochloride  it  gives  a  yellow 
flocculent  precipitate,  which  soon  crystallizes  in  long  bril- 
liant yellow  needles.  This  reaction  takes  place  readily  in 
solutions  of  1  to  1000,  and  only  after  some  hours  in  solu- 
tions of  1  to  10,000 ;  and  is  not  given  by  the  bases  of  the 
pyridic  and  quinoliuic  series.  ^Mercuric  chloride  produces 
an  immediate  flocculent  precipitate  in  solutions  of  the  base 
having  a  concentration  of  1  to  1000 ;  but  requires  some 
time  to  appear  in  1  to  10,000.  Phosphotungstic  acid  gives 
an  immediate  white  precipitate  even  in  a  dilution  of  1  to 
10,000.  Phosphoraolybdic  acid  in  solutions  of  the  same 
strength  yields  a  yellow  precipitate. 


172  PTOMAINES. 

The  physiological  action  of  this  base  has  been  examined 
by  R.  WuRTZ,  who  found  the  lethal  dose  for  rabbits,  etc., 
to  be  about  one  gram  per  kilogram  of  body  weight.  It 
produces  stupor,  paralysis,  which  at  first  appears  in  the 
rear  extremities;  the  sensibility  becomes  diminished  and 
the  pupils  are  dilated  and  unresponsive  to  light ;  the  rate 
of  heart  beat  is  lowered,  and  the  rectal  temperature  falls  as 
low  as  35° ;  death  follows  a  more  or  less  prolonged  coma. 

Tanret  obtained  by  the  action  of  ammonia  on  glucose 
a  number  of  bases  to  which  he  applied  the  generic  name 
of  glucosines.  One  of  these,  having  the  formula  Cj^HjoNg 
(0==  6),  corresponds  in  its  formula  and  its  general  proper- 
ties to  Morin's  base  C^Hj^Ng  (0  =  12),  and,  in  fact,  the 
two  bases  are  considered  by  Tanret  to  be  identical. 

It  is  interesting  to  note  in  this  connection  that  alkaloidal 
bases  have  been  found  in  petroleum  by  Bandrowski,  and 
that  similar  basic  substances  have  been  detected  by 
Weller  in  paraffine  oil. 

Most  of  the  solvents  in  common  use,  such  as  alcohol,  ether, 
chloroform,  benzole,  petroleum  ether,  amyl  alcohol,  etc., 
have  been  shown  at  diiferent  times  to  contain  basic  pyri- 
dine compounds,  though  ordinarily  in  very  minute  quantity. 
On  the  other  hand,  Haitinger  has  found  in  some  speci- 
mens of  amyl  alcohol  as  much  as  0.5  per  cent,  of  pyridine. 


Methyl-guanidine,  C^H^Ng  =  NH=C^^^    ^^^K 

— This  base  has  long  been  known  as  a  product  of  the  oxida- 
tion of  creatine  and  creatinine,  but  had  never  been  met 
with  in  animal  tissues.  Brieger  (III.,  33)  has  obtained 
it  from  horseflesh  which  was  allowed  to  decompose  in  a  closed 
vessel  at  a  low  temperature  ( —  9°  to  +  5°)  for  four  months. 
BocKLiscH  {Ber.  20,  1441)  has  obtained  it  from  impure 


METHYL-GUANIDINE.  173 

cultures  on  bcef-brpth  of  Flxkler  aud  Trior's  vibrio 
proteus,  containing  ordinary  putrefaction  bacteria,  for  twenty 
to  tliirty  days  at  37°-38°.  Vibrio  proteus  alone  seems  in- 
capable of  forming  this  base.  The  comma  bacillus  after 
some  time  (six  weeks)  partially  decomposes  creatinine  with 
formation  of  a  small  quantity  of  methyl-guanidine. 

It  occurs  in  the  mercuric  chloride  filtrate  (Brieger), 
from  which  it  is  obtained,  after  the  removal  of  the  mercury 
by  hydrogen  sulphide,  by  precipitation  with  phospho- 
molybdic  acid.  The  precipitate  is  decomposed  with  neutral 
lead  acetate,  and  the  filtrate  from  this,  after  removal  of  the 
lead  by  hydrogen  sulphide,  is  concentrated  and  then  sodium 
picrate  added.  The  resinous  picrate  precipitate  is  purified 
by  boiling  with  much  water,  and,  finally,  it  is  recrystallized 
from  boiling  absolute  alcohol.  According  to  Bocklisch, 
it  occurs  in  the  mercuric  chloride  precipitate  (not  in  the 
filtrate),  from  which  it  is  isolated,  after  removal  of  the 
mercury  and  concentration  of  the  clear  filtrate,  by  precipi- 
tation with  sodium  picrate.  The  precipitate  containing 
cadaveriue,  methyl-guanidine,  aud  creatinine,  is  boiled  with 
absolute  alcohol  (cadaveriue  picrate  is  insoluble)  and  the 
alcoholic  solution  is  then  evaporated  to  drive  off  alcohol 
and  taken  up  with  water.  From  this  aqueous  solution, 
after  removal  of  picric  acid,  methyl-guanidine  is  precipi- 
tated by  gold  chloride,  whereas  creatinine  remains  in 
solution. 

This  ptomaine  is  identical  with  the  synthetic  methyl- 
guanidine  (methyluramine)  which  can  be  readily  obtained  by 
boiling  a  creatine  solution  with  mercuric  oxide  or  with  lead 
dioxide  and  dilute  sulphuric  acid  (Dessaignes).  The  parent 
substance  of  methyl-guanidine  as  it  occurs  in  putrefaction  is 
undoubtedly  the  creatine  which  exists  preformed  in  the 
muscular  tissue.     If  such  is  the  case,  the  bacteria  engaged 

15* 


174  PTOMAINES. 

in  its  production  must  be  considered  a^  possessing  an  oxi- 
dizing action,  since  this  base  is  prepared  synthetically  from 
creatine  by  oxidation.  That  creatine  does  not  offer  much 
resistance  to  the  action  of  bacteria  is  shown  in  the  fact  that 
Friedlander's  pneumonia  coccus,  which  possesses  but 
small  chemical  powers,  is  capable  of  slowly  but  steadily  de- 
composing creatine,  yielding  as  one  of  the  products  acetic 
acid.  Strecker  and  Erlenmeyer,  as  well  as  Baumann, 
have  shown  that  creatine,  although  a  substituted  guanidine, 
is  not  poisonous,  but  it  is  readily  converted  into  creatinine, 
which  is  a  relatively  toxic  substance.  On  the  other  hand, 
guanidine  and  methyl-guanidine  are  quite  violent  poisons. 
This  is,  therefore,  another  instance  in  which  a  toxic  sub- 
stance is  formed  by  the  action  of  bacteria  from  a  previously 
non-poisonous  base  (see  page.  190).  According  to  Lossen, 
guanidine  is  formed,  although  in  small  quantity,  in  the 
oxidation  of  albumin. 

The  formulae  of  these  closely  related  substances  are  here 
given  for  comparison  : 

Creatine,  nH=C<^(™3).CH,.C0,H 


/N(CH3).CH2 
Creatinine,  NH=C<f    ^       '    i      ' 
\NH  —  CO 


Methyl-guanidine,  NH=C<™-^^3 


Guanidine,  NH=Cv  Ty^p-' 


Methyl-guanidi^^e  forms  a  colorless,  easily  deliquescent 
mass  possessing  a  strong  alkaline  reaction.  On  heating 
with  potassium  hydrate  it  decomposes,  and  yields  ammonia 
and  methylamine.     It  is  a  highly  poisonous  base. 


METHYL-GUANIDINE.  175 

The  Hydrochloride,  CgH^Ng.HCl,  can  be  obtained 
from  the  picrate  by  dissolving  the  latter  in  water  acidulated 
with  hydrochloric  acid,  and  extracting  the  solution  with 
ether  to  remove  the  picric  acid.  The  colorless  aqueous  solu- 
tion now,  on  evaporation,  yields  a  thin  syrup  wdiich  crys- 
tallizes in  vacuum  to  compact  prisms.  These  are  insoluble 
in  alcohol,  and  give  with  platinum  chloride  a  double  salt  of 
mouoclinic  needles  (Haushofer)  which  are  very  easily 
soluble  (1  part  in  about  7  parts  water,  Tatarinow). 

The  AuROCHEORiDE,  C^H.Nj.HCl.AuClg  (An  =  47.70 
per  cent.),  forms  rhombic  crystals  (Haushofer)  which  are 
easily  soluble  in  ether,  more  difficultly  in  water  or  alcohol. 
It  readily  decomposes  on  heating  in  pure  water,  but  may 
be  recrystallized  from  water  acidulated  with  hydrochloric 
acid.     It  melts  at  198°. 

The  Picrate,  C2H7N3.C6H2(N02)30H,  comes  down  at 
first  as  a  resinous  precipitate,  which  when  boiled  wnth  much 
water  solidifies  in  the  form  of  felted  needles.  It  is  very 
difficultly  soluble  in  water,  and  can  be  purified  by  repeated 
recrystallization  from  boiling  absolute  alcohol — distinction 
from  cadaverine.     It  melts  at  192°. 

The  Oxalate,  (C2H7X3)2.H2C20,+2H20,  forms  crystals 
which  are  easily  soluble  in  water. 

Physiological  Action. — Methyl-guanidine  as  ob- 
tained from  putrefying  flesh  is  identical  in  its  physiological 
action  with  the  synthetic  base.  It  has  already  been  stated 
that  the  non-poisonous  creatine  is  readily  converted  into  the 
relatively  energetic  poison  creatinine.  The  latter  substance 
possesses  a  paralyzing  action  differing  very  much  from  its 
decomposition-product  methyl-guanidine.  This  base  is  very 
poisonous,  and  the  symptoms  are  marked  by  dyspnoea, 
muscle  tremor,  and  general  clonic  convulsions.  Brieger 
has  observed  the  following  symptoms  on  injection  of  about 


176  PTOMAINES. 

0.2  gram  of  methyl-guanidine  into  a  guinea-pig.  The  res- 
piration at  once  becomes  more  rapid,  and  in  a  few  minutes 
abundant  passage  of  urine  and  stool  takes  place;  the  pupils 
dilate  rapidly  to  the  maximum  and  cease  to  react.  The 
animal  is  uneasy  but  motionless,  though  not  exactly  para- 
lyzed. Respiration  becomes  deeper  and  more  labored,  the 
head  moves  from  side  to  side,  the  extremities  become  gradu- 
ally paralyzed ;  dyspnoea  sets  in,  the  animal  falls  on  its 
side  and  dies  (twenty  minutes)  amid  general  clonic  convul- 
sions of  short  duration.  Fibrillary  twitchings  of  the 
trunk  muscles  are  observed  only  in  the  beginning.  Post- 
mortem showed  the  heart  to  be  stopped  in  diastole,  the  in- 
testines filled  with  fluid,  the  bladder  contracted,  the  cortex 
of  the  kidney  hypersemic,  but  the  papillae  of  the  kidneys 
surprisingly  pale. 

A  Base,  CigNjo^i?  ^"^^^  obtained  as  early  as  1868  by 
OsER,  who  observed  its  formation  during  the  fermentation 
of  pure  cane-sugar  by  means  of  yeast.  The  hydrochloride 
when  dried  in  vacuo  is  said  to  form  a  white,  very  hygro- 
scopic foliaceous  mass,  which  soon  becomes  brown  on  expo- 
sure to  air.  At  first  it  imparts  a  burning  taste,  which  is 
soon  replaced  by  a  very  bitter  sensation. 

A  Base  corresponding  to  the  formula  C^yHggN^  was  ob- 
tained by  Gautier  and  Etard  from  the  mother  liquors  of 
the  platinochloride  of  the  base  CgH^gN.  Very  little  is 
known,  however,  in  regard  to  the  general  properties  of  this 
base,  owing  to  the  small  quantity  which  could  be  isolated. 
This  base  and  the  one  obtained  by  Oser  from  the  yeast 
fermentation  of  sugar,  CigllgoN^,  are  the  only  ptomaines 
thus  far  isolated  which  are  known  to  contain  four  atoms  of 
nitrogen. 


MYDINE.  177 

The  PlathsOciiloride,  C17H33N4.2HCl.PtCl,  (Pt  = 
27.55  per  cent.),  is  readily  soluble,  aud  cry.stallizes  in 
needles  which  possess  a  light  yellow  flesh  color.  When 
heated  to  100°,  it  slowly  decomposes,  giving  oif  a  seringa- 
like  odor. 

Mydine,  CgHjiNO,  is  a  non-poisonous  base  which  has 
been  obtained  by  Brieger  (III.,  25)  from  the  putrefaction 
of  about  two  hundred  pounds  of  human  internal  organs. 
It  occurs  in  the  mercuric  chloride  filtrate,  and  is  isolated 
from  it  after  the  removal  of  the  mercury  by  hydrogen 
sulphide,  by  precipitation  with  phosphomolybdic  acid. 
The  gummy  precipitate  which  is  produced  is  decomposed 
on  the  water-bath  with  a  solution  of  neutral  lead  acetate, 
and  the  filtrate  on  evaporation  yields  a  colorless  hydro- 
chloride, crystallizing  in  plates.  It  is  purified  by  recrystal- 
lization  of  the  picrate. 

The  free  base  is  strongly  alkaline,  and  possesses  an  am- 
moniacal  odor.  It  is  characterized  by  its  strong  reducing 
properties.  The  name  mydine  is  derived  from  i^vSau,  to 
putrefy.  With  platinum  chloride  it  gives,  after  a  time,  an 
extremely  solul)Ie  salt ;  with  gold  chloride,  a  precipitate  of 
metallic  gold.     On  distillation  it  is  decomposed. 

The  Hydrochloride,  CgH,iNO.HCl,  crystallizes  in 
colorless  plates.  It  gives  a  blue  color  with  ferric  chloride 
aud  potassium  ferricyanide. 

The  Picrate,  C3HnNO.C6H2(ISr02)30H,  is  obtained  in 
broad  prisms,  which  melt  at  195°.  It  is  the  only  salt 
suitable  for  manipulations. 

In  describing  Nencki's  collidiue  (page  149)  it  was  stated 
that  tyrosin  might  be  looked  upon  as  the  source  of  that 
base.  It  would  seem,  however,  to  be  more  appropriately 
the  parent  substance  of  mydine,  inasmuch  as  it  decomposes 


178  PTOMAINES. 

on  being  heated  to  270°  into  carbonic  acid  and  oxyphenyl- 
ethylamine,  CgHj^NO.  The  change  that  takes  place  can 
be  represented  by  the  equation  : 

C  H  ^  /OFT 

Tyrosin.  Oxyphenyl-ethylamine. 

A  Base,  CgHjjNOg,  was  isolated  by  E.  and  H.  Sal- 
KOWSKi  (1883)  from  decomposing  fibrin  and  meat.  In  its 
composition  it  is  isomeric  with  betaine  anhydride.  It  is 
extremely  soluble  in  water,  very  difficultly  so  in  alcohol, 
insoluble  in  ether,  and  possesses  a  semen-like  odor  and  saline 
taste.  The  aqueous  solution,  which  is  not  alkaline  in  reac- 
tion, yields  on  evaporation  a  stellate  crystalline  mass,  which 
on  standing  over  sulphuric  acid  becomes  a  white  powder, 
which  melts  at  156°.  It  dissolves  silver  oxide,  but  not 
cupric  hydrate,  thus  showing  that  it  is  not  an  amido  acid. 
Moreover,  it  does  not  give  a  precipitate  or  blue  coloration 
with  copper  acetate,  or  ammoniacal  silver  nitrate.  The 
base  does  not  seem  to  possess  a  toxic  action. 

The  Hydeochloeide,  C5lIii]Sr02.HCl,  forms  colorless, 
stellate  crystals,  which  are  permanent  in  the  air,  and  are 
extremely  soluble  in  water,  even  in  absolute  alcohol. 

The  AuEOCHLOEiDE,  C5H11NO2.HOI.  AuClg+HjO,  is 
obtained  on  slow  evaporation,  as  large,  well-formed,  beau- 
tiful dark  yellow  crystals.  They  are  probably  monoclinic, 
contain  water  of  crystallization,  and  melt  at  below  100°. 

The  Platinochloeide  gave  on  analysis  results  cor- 
responding to  the  formula  (C^HisNO^.HCO^PtCl,.  This 
may  possibly  be  due  to  the  presence  of  some  higher  homo- 
logues  of  the  base  CgHnNO^.  It  forms  fine  orange-yellow 
crystals,  which  are  very  difficultly  soluble  in  alcohol,  easily 


NEURINE.  179 

SO  iu  hot  water,  from  wliicli,  ou  cooling,  it  crystallizes  in 
beautifal  plates. 

Choline  Group. — The  following  four  bases  are  closely 
related,  and,  indeed,  starting  from  choline,  the  oldest  and 
best  known  individual,  the  remaining  bases  can  be  readily 
prepared  from  it.  jSIoreover,  they  can  all  be  prepared 
synthetically  according  to  methods  that  will  be  subsequently 
indicated.  As  choline  is  the  most  prominent  member,  we 
have  thought  best  to  class  these  substances  together  as  con- 
stituting the  choline  group.  It  is  very  probable  that  my- 
datoxine  and  mytilotoxine,  when  their  constitution  becomes 
known,  ^s'ill  be  found  to  be  homologues  of  certain  members 
of  this  group. 

Neueixe,  C5HJ3NO  =  C2H3.X(CH3)3.0H.— This  sub- 
stance was  obtained  and  name<l  thus  by  Liebreich  (1865), 
who  prepared  it  by  boiling  protagon  for  twenty-four  hours 
with  concentrated  baryta.  Previous  to  its  discovery  as  a 
decomposition-product  of  protagon  from  the  brain  it  was 
prepared  synthetically  by  Hoffmann  (1858)  by  treating 
trimethylamine  and  ethylene  bromide  with  potassium  hy- 
drate or  silver  oxide.  Baeyer  (1866),  by  boiling  an  alco- 
holic extract  of  the  brain  with  baryta  water,  obtained  on 
separation  by  three  different  methods,  a  base,  or  rather  a 
mixture  of  bases,  which,  on  analysis,  gave  results  corre- 
sponding to  the  three  formulae  : 

1.  2.  3. 

(C5Hi,NOCl)2PtC],       (C5H,2XCl).,PtCl,       (C5Hi,XCl)2PtCh 

Formula  No.  3  was  the  one  accepted  by  Liebreich  for 
neurine,  but,  according  to  Baeyer,  Liebreich's  neurine 
salt  is  not  simple,  but  is  a  mixture  of  Xos.  1  and  2.     He, 


180  PTOMAINES. 

himself,  accepts  formula  No.  1  as  the  platinochloride  of 
neurine,  and  distinctly  states  (Anna!,  d.  Cliem.  u.  Pharm., 
142,  323, 1867)  that  neurine  is  in  composition  trimethyloxy- 
ethyl-ammonium  hydroxide.  And,  according  to  him,  cho- 
line from  bile,  and  sinkaline  from  white  mustard,  appear 
to  be  identical  with  neurine. 

This  nomenclature  of  Baeyer's  was  at  first  adopted  by 
WuRTZ  and  others,  who  showed  that  the  oxyethyl  base 
was  identical  with  choline  and  sinkaline.  On  that  account 
Strecker,  in  1868  [Annal.,  148,  79),  suggested  the  restric- 
tion of  the  name  choline  to  the  oxyethyl  base,  and  to 
reserve  the  name  neurine  for  the  base  whose  platinochloride 
is  represented  in  No.  3,  as  originally  was  done  by  Lieb- 
reich.  In  1869  Liebreich  showed  conclusively  that 
pure  protagon,  when  heated  with  baryta  for  twenty-four 
hours,  yields  a  substance  having  the  composition  of  the 
vinyl  base  : 

F(CH3)3.C,H3.0H. 

The  platinochloride  of  this  base  crystallized  in  five-sided 
yellow  plates,  which,  after  a  time,  on  exposure  to  the  air, 
became  cloudy ;  on  treatment  now  with  water  a  portion 
dissolved,  and  the  solution  was  found  to  contain  the  oxy- 
ethyl base.  Furthermore,  he  observed  that  when  the  alco- 
holic extract  of  the  brain,  from  whicli  all  the  protagon  had 
been  removed,  is  treated  with  baryta,  only  the  latter,  the 
oxyethyl  base,  is  obtained.  Finally,  in  1870,  Wurtz 
abandoned  the  use  of  the  term  neurine  to  designate  the 
oxyethyl  base,  and  returned  to  the  name  choline,  originally 
applied  to  the  oxyethyl  base  by  its  discoverer,  Streoker. 
Nevertheless,  the  confusion  in  the  use  of  these  two  terms 
continued  to  exist,  and  even  at  the  present  time  it  is  the 
cause  of  no  little  misunderstanding.    Thus,  Marino-Zuco 


NEURINE.  181 

(1885),  in  his  excellent  researches  on  the  genesis  of  pto- 
maines, applies  the  term  neurine,  following  Baeyer's  pre- 
cedent, to  the  oxyethyl  base,  CgHjjNOg,  which  is  really 
choline,  according  to  the  proper  nomenclature. 

We  have  gone  somewhat  at  this  point  in  detail  into  the 
history  and  the  proper  use  of  the  terms  neurine  and  choline 
because  of  the  confusion  which  is  sure  to  arise  if  the  dis- 
tinction is  not  thoroughly  borne  in  mind.  The  name 
neurine,  then,  should  be  used  only  to  denote  the  vinyl  base 
CgHjgNO.  It  is  triraethyl-vinyl-ammonium  hydrate.  On 
the  other  hand,  choline  is  applied  to  the  oxyethyl  base 
C5H15NO2,  which  is  trimethyl-oxyethyl-ammonium  hydrate. 

Neurine  has  been  obtained  by  Brieger  in  the  putre- 
faction of  horse,  beef,  and  human  flesh  for  five  to  six  days 
in  summer.  It  also  occurs  in  the  commercial,  so-called 
"neurine,"  together  with  choline  (Brieger,  I.,  34).  Lieb- 
REICH  obtained  it  in  the  decomposition  of  protagon  by 
baryta.  And  Brieger  (I.,  60)  also  has  isolated  it  along 
with  choline  from  fresh  human  brains,  by  boiling  with 
baryta;  but  has  not  obtained  it  by  digesting  the  brains  on 
the  water-bath  with  two  per  cent,  hydrochloric  acid. 

The  genesis  of  neurine  is  still  rather  obscure,  and  it  is  to  be 
hoped  that  future  investigations  may  shed  more  light  upon 
the  mysterious  production  of  this  highly  poisonous  base. 
Its  occurrence  in  the  brain  too-ether  with  choline  would 
seem  to  indicate  that  it  is  either  derived  from  choline  by 
the  removal  of  water,  or  that  it  exists  together  with  choline, 
partly  replacing  the  latter  in  the  molecule  of  protagon 
(lecithin),  according  to  the  hypothesis  put  forward  by 
LiPPMANN  (page  188).  The  question  of  its  derivation  from 
choline  by  withdrawal  of  a  molecule  of  water  has  already 
been  subjected  to  an  interesting  experimental  discussion. 
Ch.  Gram  attempted  to  explain  the  production  of  neurine 

16 


182  PTOMAINES. 

and  other  muscarine-like  ptomaiDes  as  due  to  the  dehydrat- 
ing action  of  the  acids  employed  in  the  methods  of  ex- 
traction, and,  indeed,  he  claimed  to  have  converted  choline 
platinochloride,  by  heating  with  hydrochloric  acid,  into 
neurine.  This  statement  has  been  disputed  by  Beieger, 
who  showed  that  the  jjlatinochloride  of  choline,  as  well  as 
the  hydrochloride,  may  be  heated  with  iifteen  or  thirty  per 
cent.,  or  even  concentrated  hydrochloric  acid,  for  six  to 
eight  hours  on  a  water-bath,  without  any  conversion  what- 
ever (III.,  15).  That  neurine  may  be  obtained  from 
choline,  at  least  by  chemical  processes,  was  shown  by 
Baeyer,  in  1866,  who  found  that  choline  chloride,  when 
heated  with  several  times  its  volume  of  concentrated  hydri- 
odic  acid  and  some  red  phosphorus,  gave  a  compound 
CjHjgNIg,  which,  on  digestion  with  fresh,  moist  silver 
oxide,  yielded  a  vinyl  base  identical  wdth  that  previously 
obtained  synthetically  by  Hoffmann,  and  now  known  as 
neurine.  Brieger  has  tried,  unsuccessfully,  to  bring  about 
this  dehydration  by  the  putrefaction  of  pure  choline  (I., 
59).  However,  Schmidt  and  Weiss  (1887)  were  more 
successful,  and  they  found  that  choline,  as  well  as  the 
hydrochloride  and  lactate,  is  changed  by  the  action  of 
microorganisms  into  the  strongly  poisonous  neurine.  Their 
results  are  given  in  full  under  choline  (see  page  190). 

Neurine  is  almost  invariably  accompanied  by  choline, 
from  which,  however,  it  can  be  readily  separated  by  the 
difference  in  the  solubilities  of  the  platinochlorides.  It 
occurs  in  the  mercuric  chloride  precipitate  (and  in  the 
filtrate),  and  from  this  it  can  be  obtained,  after  removal  of 
the  mercury,  by  precipitating  the  solution  of  the  mixed 
hydrochlorides  in  absolute  alcohol  by  platinum  chloride. 
The  platinochlorides  are  then  separated  by  recrystallization 


NEURINE.  183 

from  water,  siuce  the  neiiriue  is  difficultly  soluble,  whilst 
the  choline  salt  is  readily  soluble. 

The  free  base  possesses  a  strong  alkaline  reaction,  and 
on  contact  with  the  fumes  of  hydrochloric  acid  it  yields  a 
cloud.  Accordincr  to  Liebreich,  the  alkaline  solution 
cannot  be  neutralized  by  passing  through  it  carbonic  acid. 

The  Chloride,  CgHiji^.Cl,  is  extremely  poisonous,  and 
crystallizes  in  fine  hygroscopic  needles. 

The  Platinochloride,  (C5H,,X.Cl)2PtCl,  (Pt=33.96 
per  cent.),  is  difficultly  soluble  in  hot  water,  and  crystallizes 
in  beautiful,  well-formed  octahedra  belono-iuo;  to  the  reg-ular 
system.  No  twin-crystals  are  observed.  Sometimes  the 
crystals  contain  water  of  crystallization,  at  other  times  they 
do  not  (Brieger,  T.,  33).  According  to  Liebreich,  it 
forms  from  an  aqueous  solution  in  five-  or  six-sided,  heaped- 
up  plates  resembling  urea  nitrate,  whilst  from  an  alcoholic 
solution  it  forms  needles,  which  on  exposure  to  air  become 
opaque,  and  are  partially  converted  into  the  oxyethyl  base 
— choline. 

The  AuROCHLORiDE,  CgHi^^.Cl.AuClg  (Au=46.35 
per  cent.),  forms  flat  prisms,  which  are  difficultly  soluble 
in  hot  water  (Brieger).  Dissolves  easily,  and  can  be 
purified  by  crystallization  (Liebreich). 

PHYSiOTiOGiCAL  AcTiON. — Ncurine  is  exceedingly  pois- 
onous, even  in  small  doses,  and  in  its  action  it  strongly 
partakes  of  the  characteristic  stamp  of  poisoning  by  musca- 
rine. The  injection  of  a  few  milligrams  into  frogs  produces 
in  a  short  time  a  complete  paralysis  of  the  extremities,  with 
deadening  of  reflex  excitability.  Respiration  .stops  first, 
whilst  the  rate  of  heart-beat  gradually  decreases  till,  finallv, 
a  stoppage  in  diastole  takes  place.  The  injection  of  atropine 
at  this  point  does  away  with  the  effect  of  neurine,  so  that 
the   heart  begins  to  beat  again.     Previously   atropinized 


184  PTOMAINES. 

frogs,  as  a  rule,  withstaud  the  action  of  the  poison.  Im- 
mediately after  the  introduction  of  this  substance  there  can 
be  observed  a  distinct  period  of  exaltation,  which,  however, 
soon  gives  way  to  the  characteristic  stage  of  depression,  seen 
in  the  progressive  slowing  of  the  rate  of  heart-beat.  Of 
the  warm-blooded  animals,  cats  seem  to  be  much  more 
sensitive  to  its  action  than  mice,  rabbits,  or  guinea-pigs. 
The  symptoms  seen  in  rabbits  are  profuse  moistening  of  the 
nasal  cavities  and  upper  lip,  which  is  succeeded  by  an 
intensely  profuse  salivation ;  later  on  there  is  noticeable  an 
abundant  secretion  from  the  nasal  mucous  membrane  and 
from  the  eyes ;  the  latter,  however,  ceases  in  a  short  time. 
The  movements  of  the  heart  and  of  respiration  are  at  first 
quickened  and  strengthened,  but  before  long  the  paralytic 
effects  produce  a  constant  slowing  and  weakening,  till 
finally  complete  cessation  of  both  movements  results.  The 
decided  dyspnoea  observed  gradually  alters  its  character, 
and  just  before  death  the  respiration  is  irregular  and  super- 
ficial. The  heart,  as  in  frogs,  continues  to  beat  after  the 
respiratory  movements  have  ceased,  till  finally  it  stops  in 
diastole.  Direct  application  of  concentrated  solutions  of 
the  poison  to  the  eyes  produces  almost  always  a  contraction 
of  the  pupil,  whilst  a  similar  but  less  constant  contraction 
is  seen  when  it  is  injected.  The  peristaltic  action  of  the 
intestines  is  heis:htened  to  such  an  extent  that  continual 
evacuation  takes  place.  Just  before  death,  violent  clonic 
convulsions  occur.  Atropine  possesses  a  strong  antagonistic 
action  toward  neurine,  and  the  injection  of  even  a  small 
quantity  is  sufficient  to  dispel  the  symptoms  just  described. 

Choline,    CsHj^NO^  =  C2HpH.N(CH3)3.0H.— This 

base  is  identical  with  the  sinkaline  of  von  Babo,  the  bili- 
neurine   of    LiEBEEtCH,    and   the    neurine   of    Baeyer, 


CHOLINE.  185 

Marixo-Zuco,  and  others.  According  to  Schmiedeberg 
and  Harnack,  it  is  identical  with  Letellier's  amanitine 
(agaricine),  to  whieii  they  assign,  however,  the  formula 
(CH3)3N.(CHOH.CH3)OH.  Choline  was  first  prepared, 
and  so  named,  by  Strecker,  in  1862,  by  treating  hog-bile 
with  hydrochloric  acid.  It  was  prepared  synthetically  by 
WuRTZ  (1868)  by  direct  union  of  ethylene  chlorhydrine 
and  trimethylamine.  The  reaction  that  takes  place  can  be 
represented  by  the  equation  : 


31  „       ch!1 


C^H.I'^Jf     +      CH,  VN=         XJi'lNCl, 

Baeyer  (1866)  obtained  it  by  boiling  an  alcoholic  extract 
of  the  brain  with  baryta  water;  and  Liebreich,  in  1869, 
showed  that  if  the  alcoholic  extract,  from  which  all  the 
protagou  had  been  removed,  be  thus  treated,  only  choline  is 
formed,  whereas  pure  protagou,  on  heating  with  baryta, 
yields  neurine.  It  has  been  obtained  from  the  yolk  of 
eggs ;  from  bile  ;  from  fresh  brains  (Brieger)  ;  from  fresh 
eggs,  blood,  lungs,  and  hearts,  and  lecithin  (Marino- 
Zuco) ;  from  human  placenta  (Boehm)  ;  from  commercial 
neurine  (Brieger)  ;  from  fresh  as  well  as  decomposing 
internal  organs  of  the  cadaver  (Brieger)  ;  from  herring- 
brine  and  decomposing  pike,  three  days  in  midsummer 
(Bocklisch).  It  has  also  been  isolated  from  cultures 
of  vibrio  proteus  (Bocklisch),  and  of  comma  bacillus 
(Brieger). 

Not  only  has  choline  been  met  with  in  the  animal  tissues, 
but  it  has  also  been  observed  within  the  last  few  years  to 
be  very  widely  distributed  in  the  vegetable  kingdom. 
Thus,  it  has  been  found  (Harnack,  1876)  accompanying 
muscarine,  in    toad-stool  (Agaricus  muscarius) ;   in    hops, 

16* 


186  PTOMAINES. 

and  hence  in  beer  (Geiess,  Harrow)  ;  iu  the  seeds  of 
Trigonella  (Jahns)  ;  of  white  mustard  as  a  glycoside  (von 
Babo)  ;  in  ergot  (Brieger)  ;  in  the  germs  of  pumpkins 
and  lupines  (Suhulze,  Zeitschr.  f.  Physiol.  Chem.,  11,  365); 
in  Indian  hemp  (Jahns)  ;  in  beech-nuts  and  morels  (Hel- 
vella  esculenta,  Bohm)  ;  in  Flores  Sambuci,  and  extracts  of 
belladonna  and  hyoscyamus  (Kunz),  and  Scopolia  Japonica 
(Schmidt  and  Henschke).  According  to  Lippmann 
(Ber.  20,  3206),  it  is  present,  together  with  betaine,  iu  the 
molasses  from  beet-root  sugar.  Choline  (Ritthausen) 
and  betaine  (Bohm)  exist  together  in  cotton-seeds;  hence 
choline  occurs  in  the  press-cakes  from  cotton-seeds  (Bohm). 

Choline  may  readily  be  prepared,  after  the  method  of 
DiAKONOW,  from  the  yolk  of  eggs.  These  are  extracted 
with  ether,  then  with  alcohol,  and  the  extracts  thus  ob- 
tained are  evaporated,  and  the  resulting  residues  are  boiled 
with  baryta  for  one  hour.  The  filtrate,  after  the  removal 
of  the  barium  by  carbonic  acid,  is  evaporated  and  the 
residue  is  extracted  with  absolute  alcohol.  The  alcoholic 
solution  is  now  precipitated  with  platinum  chloride. 
Brieger  (II.,  55)  has  presented  a  method  which  is  much 
simpler  in  its  details  and  obviates  the  use  of  the  expen- 
sive platinum  chloride.  The  tissues  rich  in  lecithin,  as 
yolk  of  egg,  brain,  etc.,  are  heated  with  concentrated 
hydrochloric  acid  for  some  hours  on  the  water-bath.  The 
insoluble  residue  is  filtered  off,  and  the  filtrate,  after  neu- 
tralization of  the  excess  of  free  acid  with  carbonate  of 
sodium,  is  evaporated.  The  residue  is  extracted  with 
alcohol,  and  the  alcoholic  solution  is  precipitated  with 
alcoholic  mercuric  chloride.  The  precipitate  thus  obtained, 
on  recrystallization  several  times  from  a  large  quantity  of 
boiling  water,  yields  the  pure  double  salt  of  choline. 

In  regard  to  the  geijesis  of  choline  the  preponderance  of 


CHOLINE  187 

testimony  goes  to  show  that  it  is  derived  from  the  decom- 
position of  lecithin,  which,  according  to  the  researches  of 
DiAKONOW  and  others,  is  one  of  the  most  widely  distributed 
compounds,  occurring  in  greater  or  less  quantity  in  all  of 
the  animal  tissues.  Lecithin,  which  is  a  complex  esther, 
decomposes  under  the  action  of  acids  and  alkalies  into  a 
base  (choline),  glycerine,  phosphoric  acid,  and  fatty  acids 
(stearic,  oleic,  palmitic,  etc.).  This  change,  which  is  readily 
brought  about  in  the  laboratory,  is  undoubtedly  accom- 
plished in  a  similar  manner  through  the  agency  of  bacteria. 
Brieger  (II.,  17)  is  inclined  to  believe  that  choline  exists 
preformed  in  the  various  tissues,  inasmuch  as  he  has  been 
unable  to  obtain  it  from  the  brain,  which  is  rich  in 
lecithin,  by  boiling  with  two  per  cent,  hydrochloric  acid. 
Prolonged  heating  with  concentrated  hydrochloric  acid  was 
necessary  in  order  to  obtain  any  choline  from  the  brain. 
This  result  of  Brieger's  is  somewhat  at  variance  with 
that  of  Marino-Zuco  (see  Relazione,  etc.,  pages  29,  30,  and 
38),  who  obtained  from  25  grams  of  lecithin,  by  the 
method  of  Stas,  a  small  quantity  of  the  aurochloride  of  a 
base,  whilst  from  a  similar  amount  he  obtained  more  relevant 
quantities  by  the  method  of  Dragendorff. 

The  occurrence  of  choline  in  the  vegetable  king^dom 
would  be  unexplainable  to  us  at  present  were  it  not  that 
we  now  know  of  the  existence  of  lecithin-like  bodies  in 
plants,  from  the  decomposition  of  which  substantially  the 
same  products  are  obtained  as  from  the  lecithin  obtained 
from  the  animal  tissues.  The  existence  of  such  a  body  in 
plants  was  first  predicted  by  Scheibler  in  1870,  who  was 
led  to  this  conclusion  in  his  celebrated  study  of  beet-root 
sugar,  because  of  the  presence  of  oleic  acid,  glycerine,  phos- 
phoric acid,  and  betaiue,  as  well  as  cholesterine,  in  the  beet- 
root extracts.     This  hypothesis  was  confirmed  by  Hoppe- 


188  PTOMAINES. 

Seyler,  who.  in  1879,  found  a  lecithin  substance  in  yeast. 
ScHULZE  found  a  similar  compound  in  the  cotyledons  of 
lupine,  whilst  Jacobson  observed  its  presence  in  mustard- 
seeds,  in  fenugreek-seeds,  in  maize  and  wheat,  in  the  fat 
from  beans,  peas,  vetch,  and  lupines.  Heckel  showed  its 
presence  in  glol)ularia,  and  Lippmann  has  found  it  in  beet- 
root. According  to  Hoppe-Seyler,  this  lecithin-like  sub- 
stance exists  in  all  vegetable  cells  undergoing  development. 
Up  to  the  present  time  lecithin  has  always  been  supposed 
to  contain  a  radical,  which  gives  rise  to  choline  on  saponifi- 
cation, as  an  essential  component,  whilst  on  the  other  hand 
the  fatty  acids  entering  its  molecule  are  well  known  to  be 
replaceable  by  one  another.  Thus  we  may  have  a  di- 
stearine  lecithin  as  well  as  a  di-oleine  lecithin.  Recent  ob- 
servations of  LiPPMANN  {Ber.  20,  3206)  show  that  the 
above  basic  radical,  hitherto  regarded  as  constant  in  lecithin, 
may  possibly  be  capable  of  replacement  by  other  similar 
radicals.  He  found  on  saponifying  with  baryta  two  dif- 
ferent specimens  of  lecithin,  both  obtained  from  beet-root, 
that  whilst  one  of  them  yielded  oleic  acid,  glycerine,  phos- 
phoric acid,  and  betaine ;  the  other  lecithin  gave  oleic  acid 
(and  some  other  fatty  acids),  glycerine,  phosj)horic  acid,  and 
choline,  with  no  betaine — at  least  not  in  isolable  quantity. 
This  remarkable  difference  has  led  Lippmann  to  suggest 
an  explanation  which,  while  it  may  not  be  the  correct  one, 
nevertheless  possesses  a  high  degree  of  probability.  Accord- 
ing to  him,  the  lecithin  molecule  may  contain  interchange- 
aljle  basic  radicals  in  the  same  manner  that  it  contains 
interchangeable  acid  radicals.  This  view  is  supported  not 
only  in  the  case  of  beet-root,  where  choline  and  betaine 
exist  together,  but  the  same  two  bases  have  been  observed 
in  cotton-seeds.  A  similar  coexistence  was  observed  in  the 
toad-stool  (Agaricus  n^uscarius),  in  which  choline  and  mus- 


DECOMPOSITIONS    OF    CHOLINE.  189 

carine  were  found.  And,  lastly,  the  same  condition  holds 
true  probably  for  raytilotoxiue  and  betaiue,  which  were 
shown  to  be  present  together  in  poisonous  mussel. 

Lecithin  cannot  always  be  regarded  as  the  source  of 
choline  in  plants,  since  this  base  is  known  to  occur  as  a 
glucoside  in  the  seeds  of  white  mustard.  The  sinapin  de- 
composes according  to  the  equation  : 

Sinapin.  Choline  Sinapic  Acid. 

Decompositions  of  Choline. — Baeyer  (1866)  suc- 
ceeded in  converting  choline  into  neurine  by  a  purely 
chemical  process.  This  was  accomplished  by  heating 
choline  chloride  with  concentrated  hydriodic  acid  and 
red  phosphorus  in  a  sealed  tube  at  120°-150°,  whereby 
the  compound  C5Hj3Nl2  was  formed.  The  iod-iodide  of 
choline  thus  obtained,  on  treatment  with  moist  silver  oxide 
gave  a  base  whose  platinochloride  corresponded  to  the 
formula  (CsHi^NCO.PtCl,  +  H^O.  This  double  salt,  ac- 
cording to  Baeyer,  is  readily  soluble  in  water,  and  gives 
reactions  similar  to  choline.  Although  Baeyer  is  em- 
phatic in  his  assertion  that  this  is  the  vinyl  compound 
(neurine)  formed  from  the  oxy-ethyl  base  (choline),  yet  it 
seems  that  there  is  room  for  doubt  in  regard  to  the 
interpretation  of  his  results.  Thus  neurine  platinochloride 
is  difficultly  soluble  in  water,  contrary  to  the  behavior  of 
the  platinochloride  obtained  by  him.  On  the  other  hand, 
choline  platinochloride  is  easily  soluble  in  water,  and  it 
would  seem,  therefore,  that  Baeyer  has  not  converted 
choline  into  neurine,  but  rather  has  regenerated  choline 
from  its  iod-iodide.  If  such  were  the  case,  we  would  ex- 
pect that  the  iod-iodide  of  neurine,  CgHjjNIj,  which  has 
the  same  composition  as  the  corresponding  derivative  of 


190  PTOMAINES. 

choliue,  would  yield,  on  treatment  with  silver  oxide,  the 
oxy-ethyl  base.  Baeyer  has  apparently  not  been  able  to 
effect  this  change,  since  he  holds  that  the  vinyl  base  may 
be  prepared  from  the  oxy-ethyl,  but  that  the  reverse,  the 
preparation  of  the  oxy-ethyl  base  from  the  vinyl  compound, 
cannot  be  accomplished. 

Whether  the  change  described  by  Baeyer  takes  place  or 
not,  it  is,  nevertheless,  certain  that  choline  does  not  readily 
give  up  a  molecule  of  water  and  thus  become  converted 
into  neurine.  Ch.  Gram  announced,  in  1886,  that  choline 
chloride  and  lactate  on  heating  on  the  water-bath 
decompose,  and  that  this  conversion  into  the  vinyl  base  was 
complete  when  the  aqueous  hydrochloric  acid  solution  of 
choline  platinochloride  was  heated  for  five  or  six  hours  on 
the  water- bath.  In  this  way  Gram  endeavored  to  explain 
the  formation  as  due  to  the  action  of  acids  upon  choline, 
but  Brieger  has  shown  that  the  platinum  salt  of  choline, 
as  well  as  its  hydrochloride,  can  be  heated  with  fifteen  or 
thirty  per  cent.,  or  even  concentrated  hydrochloric  acid  for 
six  or  eight  hours  without  undergoing  any  change  into 
neurine,  thus  disproving  the  results  obtained  by  Gram. 
E.  Schmidt  has  confirmed  Brieger's  observations  in 
regard  to  the  resistance  of  choline  to  decomposition  by 
acids,  but  he  has  gone  further,  and  has  shown  that  what 
the  action  of  acids  has  failed  to  do  is  readily  accomplished 
through  the  agency  of  bacteria.  He  found  that  choline 
chloride,  when  allowed  to  stand  with  hay  infusion,  or  with 
dilute  blood  for  fourteen  days  at  30°-35°,  is  almost  entirely 
decomposed  yielding  large  quantities  of  trimethylamine 
and  a  base  whose  platinochloride  resembles  in  form  and 
solubility  the  double  salt  of  neurine,  and  possesses  a 
similar  physiological  action.  Choline  lactate  in  hay  infu- 
sion developed  an  odor  of  trimethylamine  in  twelve  hours, 


DECOMPOSITIONS    OF    CHOLINE.  191 

but  at  the  end  of  fourteen  days  a  good  deal  of  choline  was 
still  present.  In  this  case  no  neuriue  was  present,  but 
instead  a  homologous  base  was  found,  which  can  be  obtained 
synthetically  i)y  the  action  of  trimethylamine  on  allyl 
bromide.  According  to  Meyer,  of  Marburg,  this  base 
does  not  possess  the  rauscarine-like  action  of  neurine,  but 
resembles  more  closely  pilocarpine. 

Brieger  (I.,  59)  had  unsuccessfully  tried  to  transform 
choline  into  neurine  by  putrefaction.  He  observed  that  the 
choline  decomposed  with  extreme  slowness,  even  when  the 
putrefaction  was  carried  on  at  a  higher  temperature,  yield- 
ing only  trimethylamine.  WuRTZ  (1868)  showed  that 
dilute  solutions  of  free  choline  can  be  heated  to  boiling 
without  any  perceptible  decomposition.  Concentrated 
solution.s,  however,  decompose  with  the  formation  of  tri- 
methylamine and  glycol,  C^RiiOH^-  The  decomposition 
of  choline  was  studied  somewhat  by  Mauthner  (1873), 
who  confirmed  AVuRTz's  observation  that  choline  was 
scarcely  decomposed  by  boiling  water,  and  he  showed  that 
when  exposed  to  the  action  of  decomposing  blood  it  yielded 
trimethylamine.  The  results  obtained  by  K.  Hasebroek 
{Ze'itschrift  f.  Physiol.  Chem.,  12,  151,  1888)  deserve  special 
mention  at  this  place.  He  carried  on  the  putrefaction  of 
very  dilute  solutions  of  the  chloride  of  choline  in  the 
presence  of  little  or  no  oxygen  in  Hoppe-Seyler  fermen- 
tation flasks.  Sewer  slime,  because  of  its  strong  fermenta- 
tive properties,  was  used  to  induce  the  putrefaction,  and 
calcium  carbonate  was  added  to  neutralize  any  acidity  that 
might  develop  during  the  fermentation. 

The  fermentation,  as  shown  by  the  evolution  of  gases, 
lasted  for  about  three  months.  The  total  quantity  of  gas 
given  off  was  about  one  litre  from  1.17  grams  choline 
chloride.     The  gases  consisted  almost  entirely  of  carbonic 


192  PTOMAINES. 

acid  and  marsh  gas.  No  hydrogen  was  evolved.  When 
the  fermentation  ceased  the  flask  was  opened  and  several 
cubic  centimeters  of  the  almost  neutral  clear  liquid  ^vere 
injected  under  the  skin  of  a  rabbit  without  producing  the 
least  effect. 

This  liquid  distilled  wdtli  alkali  gave  methylamine 
and  ammonia.  What  is  remarkable  about  this  experiment 
was  the  total  absence  of  the  higher  amines — as,  for 
instance,  triraethylamine,  w^hich  has  been  observed  so  many 
times  as  a  decomposition-product  of  choline.  The  absence 
of  any  poisonous  base,  as  neuriue,  was  probably  largely 
connected  with  the  absence  of  oxygen. 

Free  choline  ordinarily  forms  a  strongly  alkaline  syrup 
which  combines  readily  with  acids  to  form  salts,  most  of 
Avhich  are  deliquescent.  By  oxidation  it  is  converted  into 
betaine  (see  page  196),  and  on  treatment  with  concentrated 
nitric  acid  it  gives  rise  to  muscarine  (see  page  198).  These 
reactions  can  be  represented  by  the  equations  : 


+H,0 


CH^OH 
j 

y\OH 

CH^ 

+  0,  = 

1 

N(CH3)3.0H 

Choline, 

:^(CH3)3.0H 

Betaine. 

CH^OH 

1 

1 

1 

+  0  = 

CHOH 
1 

N(CH3)3.0H 

N(CH3)3.0H. 

Muscarine. 

By  the  action  of  dilute  nitric  acid  choline  is  converted 
into  a  base,  the  platinochloride  of  which  is  eflQorescent  and 


DECOMPOSITIONS    OF    CHOLINE  193 

corresponds  to  the  formula   (C,H,oiS'203Cl)PtCl,+2H20. 

(SCHMIEDEBERG  and  HaRNACK.) 

According  to  Mauthner,  choline  resembles  the  caustic 
alkalies  in  its  action.  Although  putrefying  blood  decom- 
poses it  into  trimethylamine,  yet,  when  present  in  the  pro- 
portion of  1.4  per  cent.,  it  is  said  to  arrest  putrefaction. 
A  one  to  two  per  cent,  solution  is  said  to  dissolve  fibrin  or 
coagulated  albumen  on  boiling. 

The  free  base,  as  well  as  the  carbonate,  is  dimorphous 
and  forms  thin  plates  or  long  needles. 

The  Chloride,  C5Hi^NO.C1,  is  easily  soluble  in  M-ater 
and  in  absolute  alcohol  (separation  from  neuridine  hydro- 
chloride). It  crystallizes  over  sulphuric  acid  to  needles 
which  readily  deliquesce  in  the  air. 

The  Platinochloride,  (CsHi.NO.ClXPtCl,  (Pt  = 
31.98  per  cent.),  presents  an  interesting  case  of  trimor- 
phism.  It  crystallizes  in  monoclinic  plates  (Rixxe)  which 
are  easily  soluble  in  water,  insoluble  in  alcohol ;  also  in 
characteristic  superposed  plates,  sometimes  in  the  form  of 
orange-red  flat  prisms  (Brieger).  From  a  warm  saturated 
solution  containing  fifteen  per  cent,  alcohol  it  crystallizes 
in  regular  octahedra ;  from  aqueous  solution  on  slow 
evaporation  in  cliuorhombic  prisms  or  needles  (Hoppe- 
Seyler).  According  to  Schulze,  it  sometimes  forms 
beautiful  orange-red,  chiefly  six-sided  plates.  It  contains 
always  more  or  less  water  of  crystallization  which  it  does 
not  give  up  completely  over  sulphuric  acid,  but  only  at 
110°  (Brieger).  The  natural  platinochloride  becomes 
strongly  electric  on  rubbing,  whereas  the  synthetic  choline 
double  salt  does  not  become  electric. 

The  Aurochloride,  CsHi.NO.Cl.AuClg  (An  =  44.45 
per  cent.),  is  crystalline  and  is  difficultly  soluble  in  cold 
water,  but  can  be  recrystallized  from  hot  water  or  from 

17 


194  PTOMAINES. 

boiliDg  alcohol.  It  forms  prisms,  or  gold-yellow  long 
needles,  which  are  very  easily  soluble  in  hot  water  and 
alcohol  (Lippmann),  It  can  be  separated  from  neuridine 
aurochloride  by  its  solubility  in  water  (Beiegee).  On 
heating,  the  gold  salt  melts  to  a  brown  liquid  (Schulze) 
and  decomposes  at  264°. 

The  Meecueochloeide,  CgH^^NO.Cl.eHgClg,  is  ex- 
tremely difficultly  soluble  even  in  hot  water.  On  this 
account  the  mercury  salt  is  very  convenient  for  the  separa- 
tion of  choline  from  accompanying  bases. 

The  PiCEATE,  C5Hi4NO.OC6H2(N02)3,  forms  long 
broad  needles  which  are  more  easily  soluble  than  neuridine 
picrate,  and  hence  can  be  separated  by  recrystallization.  It 
is  more  easily  soluble  in  alcohol  than  in  water. 

Physiological  Action  of  Choline. — Choline  was 
regarded  for  a  long  time  as  physiologically  inert,  but  this 
belief  was  set  aside  by  Gaehtgens  (1870),  who  showed 
that,  when  given  in  large  quantity,  it  possessed  a  toxic 
action.  This  observation  of  Gaehtgens  has  since  been 
confirmed  by  Glause  and  Luchsingee,  Beiegee,  and 
Boehm.  The  chloride  of  choline  produces  in  animals  the 
same  muscarine- like  symptoms  of  poisoning  as  are  devel- 
oped by  the  vinyl  base  neurine,  the  only  difference  lies  in 
the  intensity  of  the  action.  In  order  to  bring  about  a 
physiological  disturbance,  choline  must  be  given  in  rela- 
tively large  doses.  Thus,  Beiegee  has  found  it  necessary 
to  give  about  0.1  gram  of  choline  chloride  hypodermic- 
ally  to  a  one  kilogram  rabbit  in  order  to  bring  out  the  same 
effects  as  are  obtained  by  the  injection  of  0.005  gram  of 
the  neurine  salt.  He  also  found  that  the  fatal  dose  for  a 
one  kilogram  rabbit  was  about  0.5  gram,  which  is  about  ten 
times  as  large  as  the  fatal  dose  of  neurine  chloride.  Boehm 
observed  that  doses  of  0.025-0.1  gram  produced  in  frogs 


BETAINE.  195 

general  paralysis,  which,  in  a  short  time,  leads  to  death  or 
recovery;  and  that  in  its  curara-like  paralyzing  action, 
choline  resembles  artificial  muscarine,  although  the  latter 
is  about  500  times  stronger.  Atropine,  as  in  the  case  of 
neurine  and  muscarine,  antagonizes  the  action  of  choline. 
Thus,  0.05  gram  of  the  chloride  produced  in  a  frog  in  one 
hour  diastolic  standstill  of  the  iieart.  This  condition  was 
removed  by  the  injection  of  0.001  gram  of  atropine,  the 
heart-beat  rising  to  the  normal  in  about  fourteen  minutes  ; 
0.05  gram  of  choline  chloride,  given  subcutaneously  to  a 
rabbit  (1250  grams)  produced  salivation,  which  lasted  but  a 
short  time,  and  did  not  affect  the  heart-beat  and  respira- 
tion ;  0.10  gram  was  necessary  to  bring  out  all  the  symp- 
toms ;  0.05  gram,  given  to  guinea-pigs,  had  no  effect  what- 
ever. 

Betaine  (Oxyneurixe),  CgHigXOg. — This  base  has 
been  well  known  for  some  time,  because  of  its  occurrence 
in  the  vegetable  kingdom.  Thus,  it  is  present  in  cotton- 
seed (BoHM,  Ritthausen,  Weger)  ;  in  beet-root  juice 
(Beta  vulgaris),  and  hence  in  beet-root  molasses  (Schei- 
bler,  1866).  It  does  not  exist  in  these  substances  as  such, 
but  is  formed  from  a  more  complex  substance  by  the  action 
of  hydrochloric  acid  or  baryta  (Ltebreich).  In  this  respect 
it  resembles  choline,  neurine,  and  probably  muscarine. 
Quite  recently,  Lippmaxn  (1887)  has  obtained  a  lecithin- 
like body  from  sugar-beet,  which,  on  heating  wath  baryta, 
gave  oleic  acid,  glycerine,  and  phosphoric  acid  (glycerine- 
phosphoric  acid),  and  betaine,  Betaine,  however,  does  not 
seem  to  be  a  constant  constituent,  inasmuch  as  on  one  occa- 
sioned he  obtained  chiefly  choline,  and  little  or  no  betaine. 
These  two  bases  also  occur  together  in  cotton-seed,  and 
this  fact  has  led  Scheibler  to  the  conclusion  that  it  is 


196  PTOMAINES. 

no  mere  chance.  Lecithin,  as  is  well  known,  may  con- 
tain variable  acid  coustituents  (oleic,  stearic,  palmitic,  etc.), 
and  reasoning  on  this  fact,  and  on  the  results  of  his  experi- 
ments, LiPPMANN  has  been  led  to  suppose  that  it  may  also 
contain  different  bases  in  variable  proportions. 

It  has  been  obtained  from  human  urine  (Liebreich, 
1869),  and  from  poisonous  mussel,  but  not  from  putrid 
mussel  (Brieger,  III.,  76).  The  method  for  its  separation 
from  mussel  is  described  on  page  202. 

Betaine  may  be  obtained  synthetically  in  several  ways : 

(1)  by  oxidation  of  choline  with  potassium  permanganate; 

(2)  by  the  action  of  methyl  iodide  on  glycocoll ;  (3)  by 
treating  monochloracetic  acid  witli  trimethylamine.  The 
last  two  methods  are  of  value  as  indicating  the  constitution 
of  betaine,  and  the  changes  which  take  place  can  be  repre- 
sented by  the  equations  : 

NH3  N(CH3)3l 

CH2        +     3CH3I     =     CR,  +     2HI 

CO2H  CO2H 


CHgCl 

I 
CO,H 


Betaine  Chioeide. 

N(CH3)3C1 


N(CH3)3    =     CH 


CO2H 


MONOCHLOEACETIC  ACID. 

From  the  formulae  of  the  salts  of  betaine  it  is  evident 
that  betaine  has  properly  the  composition  C5H,3N03,  which 
is  expressed  by  the  structural  formula : 
N(CH3)30H 

I 
CO2H 


BETAINE.  197 

This  free  base  is,  however,  readily  converted  into  the 
anhydride  C^H^NO,. 

Betaine  is  ordinarily  regarded  as  crystallizing  with  one 
molecule  of  water,  and  the  composition  is  expressed  by  the 
formula:  C^HnNO^  +  H^O  (=  OH.^XCPyj.CII^.COJI). 
It  loses  this  water  of  crystallization  by  heating  at  100°,  or  on 
standing  over  sulphuric  acid,  forming  an  anhydride  of  the 
formula  already  given.  Likbkeich  claims  that  free  betaine 
possesses  the  formula  CgHjjNOj,  because  it  yields  a  com- 
pound having  the  composition  (C5HiiN02)ZnCl2.  The  free 
base  separates  from  alcohol  in  large  crystals  which  deli- 
quesce on  exposure  to  the  air.  As  obtained  by  Brieger 
from  the  hydrochloride  by  treatment  with  moist  silver 
oxide,  it  possessed  a  sweetish  taste  and  neutral  reaction. 
When  distilled  with  potassium  hydrate,  it  yields  trimethyl- 
amine  and  other  bases,  among  which  a  base  of  the  formula 
CgHj^NOj  occurs  in  the  largest  quantity. 

The  Chloride,  CgHjgNOg.Cl,  forms  beautiful  crystals, 
raonoclinic  plates,  which  are  permanent  in  the  air,  and  this 
can  be  made  use  of  to  effect  a  separation  from  the  choline 
salt,  which  is  deliquescent.  It  is  insoluble  in  absolute 
alcohol.  This  fact  can  be  made  use  of  in  their  separation 
(Lippmann).  It  can,  moreover,  be  easily  separated  from 
other  bases  by  its  aurochloride,  which  is  easily  soluble.  If 
a  little  potassio-mercuric  iodide  is  added  to  a  solution  of 
the  chloride,  there  forms  a  clear  yellow  oily  precipitate, 
which  is  soluble  in  excess,  but  on  rubbing  the  sides  of  the 
tube  with  a  glass  rod  it  reappears  as  yellow  needles.  This 
is  said  to  be  a  characteristic  test  (Brieger). 

The  Aurochloride,  C5H,.,N02.Cl.AuCl3  (An  =  43.10 
per  cent.),  forms  magnificent  cholesterine-like  plates,  and  is 
easily  soluble  (Brieger).  The  aurochloride  from  sugar- 
beet  is  said  to  crystallize  in  needles  on  plates,  and  to  be 


198  PTOMAINES. 

difficultly  soluble  in  cold  water  (Scheibler,  Lippmann). 
The  double  salt  of  the  ptomaine  melts  at  209°,  and  in  this 
it  coincides  with  that  obtained  from  beet-sugar,  as  well  as 
with  that  of  the  synthetically  prepared  base  (Beiegbr). 
The  platinochloride  is  yellow  and  crystalline. 
Betaine  is  not  poisonous. 

Muscarine,  CgH^^NOg  =  CgHigNOg+H^O,  the  w^ell- 
known  toxic  principle  which  Schmiedeberg  obtained 
from  poisonous  mushroom  (Agaricus  muscarius),  has  been 
obtained  also  by  Brieger  (L,  48)  from  haddock  which 
had  been  allowed  to  decompose  for  five  days.  The  process 
by  which  its  isolation  was  effected  is  described  on  page  204. 
This  base  is  specially  interesting,  because  of  the  relation  it 
bears  to  choline,  for  Schmiedeberg  has  shown  that  it  is 
formed  when  choline,  or,  better  still,  the  platinochloride  is 
oxidized  by  concentrated  nitric  acid. 

The  Chloride,  C5Hj^N02.C1,  is  obtained  on  the  decom- 
position of  the  platinochloride  with  hydrogen  sulphide,  as 
a  syrupy  residue,  which,  under  the  desiccator,  shows  an 
inclination  gradually  to  crystallize.  It  is  deliquescent 
(Harnack). 

The  Platinochloride,  (CgHi.NO^.ClXPtCl^  (Pt  = 
30.41  per  cent.),  forms  as  a  crystalline  deposit  of  octahedra, 
which  are  difficultly  soluble  in  water.  They  lose  their 
water  of  crystallization  (2H2O)  only  on  strong  heating. 

The  AuROCHLORiDE,  CsHj^NOj.Cl.AuClg,  crystallizes 
in  needles,  and  is  difficultly  soluble  in  water,  more  so  than 
the  choline  double  salt  (Harnack). 

Physiological  Action. — Small  doses  of  this  ptomaine 
induce  in  frogs  total  paralysis,  with  stoppage  of  the  heart 
in  diastole,  and  this  action  is  antagonized  by  subsequent 
injection  of  atropine,  as  well  as  in  the  case  of  previously 


MEMBERS    OF    CHOLIITE    GROUP.  199 

atropinized  frogs.  Very  small  doses  produce  in  rabbits 
profuse  salivation  and  lachrymation,  contraction  of  the 
pupil,  profuse  diarrhoea,  and  passage  of  urine  and  semen ; 
finally,  the  animal  dies  in  convulsions,  which,  however,  are 
only  of  short  duration. 

CONSTITUTIOX    OF    THE     MEMBERS    OF    THE    CHOLINE 

Group. — The  structure  of  choline  was  clearly  demon- 
strated by  WuRTZ,  who  accomplished  the  synthesis  of  this 
base  by  treatment  of  ethylene  chlorhydrine  with  trimethyl- 
amine.  This  same  method  can  be  applied  to  the  synthesis 
of  betaine  and  neurine  by  using  monochloracetic  acid  and 
vinylbromide  instead  of  ethylene  chlorhydrine.  The  struc- 
tural formulae  which  can  be  deduced  from  these  reactions 
are  as  follows  : 


CH,OH 

1 

CH„                  CO^H               CII^OH 

II                        1                        1 

CH                   CH,                  CHOH 

1                           '                   1 

1 

N(CH3)3.0II 

Choiine. 

N(CH3)3.0H     N(CH3)3.0H     N(CH3)3.0H 

NeUKINE.                                 tETAtJIE.                               MUSCARINE. 

The   formulae    of   betaine   and    muscarine   are   ordinarily 

given  as  the  anhydrides,  but  there  can  be  no  doubt  that  the 

free  ba.ses  possess  the  structure  indicated  above.     All  these 

bases,  since  they  can  be  prepared  from  choline,  may  also  be 

considered  as  oxidation-products  of  trimethyl-ethyl-ammo- 

uium  hydrate  :  CHj 

I 
CH„ 

I 
N(CH3)3.0H. 

Mydatoxixe,  CgHjjNOg. — This  base  was  obtained  by 
Brieger  (III.,  25,  32)  from  several  hundred  pounds  of 


200  PTOMAINES. 

human  internal  organs  which  were  allowed  to  stand  in 
closed  but  spacious  wooden  barrels  for  four  months,  at  a 
temperature  varying  from  — 9°  to  +5°.  He  obtained  much 
larger  quantities  of  it,  however,  from  horseflesh  which  had 
putrefied  under  the  same  conditions.  In  the  process  of 
extraction  it  is  found  in  the  mercuric  chloride  precipitate 
together  with  cadaverine,  putrescine,  and  another  base, 
C7Hj7X02.  It  can  be  isolated  from  this  mixture  by  recrys- 
tallizing  the  mercury  salts,  which  removes  the  cadaverine 
because  of  its  difficult  solubility  in  water,  and  decomposing 
the  soluble  mercury  salts  by  hydrogen  sulphide.  The 
filtrate  freed  from  mercury  is  now  evaporated  to  dryness 
and  the  residue  repeatedly  extracted  with  absolute  alcohol, 
in  order  to  remove  putrescine  hydrochloride,  w'hich  is 
insoluble.  The  alcoholic  solution,  after  standing  some  time 
to  permit  complete  separation  of  any  dissolved  putrescine, 
is  then  evaporated  to  dryness  and  taken  up  with  water. 
This  solution  gives,  on  the  addition  of  gold  chloride,  a  pre- 
cijiitate  of  the  aurochloride  of  the  base  C^H^^NO^.  The 
filtrate  from  this  precipitate,  containing  the  mydatoxiue,  is 
treated  with  hydrogen  sulphide  to  remove  the  gold,  and 
then  evaporated  to  dryness.  The  colorless,  syrupy  hydro- 
chloride thus  obtained  forms  with  j)latiuum  chloride  a 
double  salt  which  is  readily  soluble  in  water,  and  can  be 
purified  by  repeated  recrystallizations  from  absolute  alcohol 
containing  some  hydrochloric  acid. 

The  name  mydatoxiue  is  derived  from  iivSau,  to  putrefy. 
The  free  base  is  obtained  from  the  hydrochloride  by  treat- 
ment with  moist,  freshly  precipitated  silver  oxide,  as  a 
strongly  alkaline  syrup,  which  solidifies  in  vacuo  to  plates. 

It  is  insoluble  in  alcohol,  ether,  etc.      It  does  not  distil 

« 

without  decomposition. 

The  HYDEOCHLORroE,  CgHigNOj.HCl,  is  a   colorless, 


MYDATOXINE.  201 

deliquescent  syrup  which  does  not  form  any  double  salt 
with  gold  chloride.  With  platinum  chloride  it  gives  an 
easily  soluble  salt.  Otherwise  it  combines  only  with  piios- 
phomolybdic  acid,  with  which  it  forms  cubes.  Ferric 
chloride  and  potassium  ferricyauide  yield,  after  a  time, 
Berlin  blue.     It  is  readily  soluble  in  alcohol. 

The  Platinochloride,  (C3Hj3NO,.HCl),PtCl,  (Pt= 
29.34  per  cent.),  melts  at  193°,  with  decomposition.  It 
crystallizes  in  plates  which  are  extremely  soluble  in  water. 
It  can  be  readily  recrystallized  from  absolute  alcohol  acidu- 
lated with  hydrochloric  acid.  The  mercury  salt  is  readily 
soluble  in  water. 

The  exact  formula  of  this  base,  of  mytilotoxine,  and 
some  other  bases,  cannot  be  considered  to  be  permanently 
settled,  inasmuch  as  the  formula  of  the  hydrochloride, 
CgHigNO^.HCl,  as  deduced  from  the  analysis  of  the 
platinum  double  salt,  may  equally  apply  to  the  base 
CgHi.NO^.OH  as  to  the  base  CgH^gNO,.  If  the  first 
formula  is  correct,  then  mydatoxine  is  a  homologue  of 
betaine,  and  its  structure  would  be  expressed  by  (1). 


(1)  (2) 

( 

H 


CO^H  C(^^ 


CH^  CH 

I  il 

CH^  CH 

I  I 

N(CH3)30H  N(CH3)30H. 

The  second  formula  would  seem  to  correspond  to  an  unsatu- 
rated aldehyde  of  the  choline  group  and  its  structure  may 
be  indicated  by  (2). 

This  ptomaine,  although  it  possesses  toxic  properties,  is 
not,  however,  a  strong  poison.    Its  action  is  the  same  as  that 


202  PTOMAINES. 

of  the  base  CyHj^NOg  (see  page  209),  with  which  it  is  associ- 
ated, except  that  the  symptoms  of  poisoning  develop  slower, 
so  that  the  death  of  a  guinea-pig  does  not  take  place  for 
about  twelve  hours.  White  mice  are  very  susceptible  to  the 
action  of  these  two  poisons.  A  short  time  after  the  injec- 
tion of  even  small  doses  they  are  taken  with  convulsions 
which  come  on  in  paroxysms.  The  eyeballs  roll  upward. 
Lachrymation,  diarrhoea,  and  dyspnoea  come  on,  and  the 
mice  die  within  a  short  time. 

Mytilotoxine,  CgHj5N02,  is  the  specific  poison  of  toxic 
mussel  (Mytilus  edulis),  from  which  it  has  been  obtained  by 
Brieger  (III.,  76).  This  poison  is  formed  during  the  life 
of  the  animal  under  certain  conditions  which  have  been 
thoroughly  studied  byScHMiDTMANN,  Virchow,  and  others 
(see  page  38).  Brieger  obtained  the  poison  by  extracting 
toxic  mussel  with  acidulous  water,  and  evaporating  this 
solution  to  a  syrupy  consistency.  The  residue  was  thor- 
oughly extracted  with  alcohol,  and  this  solution  was  treated 
with  lead  acetate,  in  order  to  remove  mucilaginous  sub- 
stances. The  filtrate  was  then  evaporated,  and  the  residue 
extracted  with  alcohol.  Any  lead  that  had  dissolved  was 
removed  by  hydrogen  sulphide.  The  alcohol  was  expelled, 
and  the  resulting  syrup  was  taken  up  with  water  and 
decolored  by  boiling  with  animal  charcoal.  The  clear  solu- 
tion was  now  neutralized  with  sodium  carbonate,  acidulated 
with  nitric  acid,  and  precipitated  with  phosphomolybdic 
acid.  The  precipitate  was  decomposed  by  warming  with 
neutral  lead  acetate,  and  the  resulting  filtrate,  after  the 
removal  of  the  lead  by  hydrogen  sulphide,  was  acidulated 
with  hydrochloric  acid'  and  evaporated  to  dryness.  The 
residue  was  extracted  with  absolute  alcohol,  whereby 
betaine,^on  account  of  its  insolubility,  is  removed,  and  the 


MYTILOTOXINE.  203 

alcoholic  solution  was  precipitated  by  alcoholic  mercuric 
chloride.  The  iiiercury  precipitate  is  repeatedly  recrystal- 
lized  from  water,  aud  the  poisou  is  obtained  as  au  easily 
soluble  double  salt. 

The  free  base  as  obtained  by  the  addition  of  alkali  to 
the  hydrochloride  possesses  a  disagreeable  odor  which  dis- 
appears on  exposure  to  air,  and  the  substance  ceases  to  pos- 
sess poisonous  properties.  Mytilotoxine  is  also  destroyed 
on  distillation  with  potassium  hydrate  and  in  the  distillate 
there  is  found  an  aromatic  non-poisonous  product.  The 
free  base,  therefore,  does  not  exist  by  itself  for  any  length 
of  time,  but  soon  becomes  converted  into  an  inert  sub- 
stance. H.  Salkowski  has  also  shown  that  it  is  destroyed 
on  boiling  with  potassium  carbonate,  whereas  its  hydro- 
chloric acid  solution  can  be  evaporated  to  dryness  and 
heated  to  110°  without  destroying  its  poisonous  property. 

The  Hydrochloride,  CgHjgNOj.HCl,  prepared  from 
the  aurochloride,  crystallizes  in  tetrahedra.  It  is  extremely 
poisonous  and  according  to  Brieger  produces  exactly  the 
same  symptoms  which  have  been  observ-ed  by  Schmidt- 
MANX  in  persons  who  have  partaken  of  poisonous  mussels 
(see  page  36).  The  ordinary  alkaloidal  reagents  produce 
in  its  solutions,  if  at  all,  only  oily  precipitates. 

As  stated  under  mydatoxiue,  the  formula  of  the  hydro- 
chloride, CgH,.N02.HCl,  is  applicable  to  either  one  of  two 
bases,  C6HigN0..dH  or  CgHj^NO..  The  base  correspond- 
ing to  the  first  formula  is  evidently  a  homologue  of  mus- 
carine, aud  should  possess  a  similar  physiological  action. 
As  a  matter  of  fact,  mytilotoxine  does  resemble  muscarine 
somewhat  in  its  action,  and  its  occurrence  together  with 
betaine  would  seem  to  make  it  a  decomposition-product  of 
lecithin,  in  which  case  this  base  must  be  looked  upon  as  a 
member  of  the  choline  group.     It  is  interesting  to  know 


204  PTOMAINES. 

that  a  compound  corresponding  to  the  formula  CgH^gNOg.OH 
has  been  known  for  some  time,  and  was  prepared  by  Han- 
riot  in  a  manner  analogous  to  Wuetz's  synthesis  of 
choline,  by  treating  glycerin  monochlorhydriue  with  tri- 
methylamine.      This    base,   trimethyl-glyceryl-ammonium 

CH2OH 

I 
CHOH 

hydrate,  has  the  structure       |  Unfortunately 

CH, 

I 
N(CH3)30H. 

it  has  not  been  studied  sufficiently  to  enable  a  comparison 
to  be  made  between  it  and  raytilotoxine. 

The  AuROCHLORiDE,  CgHi^NOa.HCl.AuClg  (Au  =  41.64 
per  cent.),  crystallizes  in  cubes.     Its  melting  point  is  182°. 

It  is  well  to  observe  that  Beieger  has  been  unable  to 
obtain  this  base  from  mussels  that  were  allowed  to  putrefy 
for  sixteen  days. 

Physiological  Action. — According  to  Beieger, 
mytilotoxine  produces  all  the  characteristic  effects  seen  in 
mussel  poisoning,  and  it  is,  therefore,  a  strong  paralysis- 
producing  poison,  and  resembles  curara  in  its  action.  For 
the  symptoms  induced  by  poisonous  mussel  see  page  36. 

Gadinine,  OyHjyNOg,  was  found  in  haddock  which  was 
allowed  to  decompose  in  open  iron  vessels  for  five  days 
during  summer.  Brieger  has  also  obtained  it  from  cul- 
tures of  the  bacteria  of  human  faeces  on  gelatine.  The  de- 
composing mass  was  thoroughly  stirred  every  day  in  order 
to  bring  it  into  contact  with  atmospheric  oxygen  (Brieger, 
I.,  49).  It  was  then  "treated  with  water,  and  hydrochloric 
acid  was  added  to  acid  reaction,  and  after  being  warmed 
the  mixture  was  filtered  and  the  filtrate  was  concentrated 


GADININE.  205 

on  the  water-bath  to  a  syrupy  consistency.  This  syrupy 
residue  was  extracted  with  water,  and  the  aqueous  solution 
was  precipitated  with  a  solution  of  mercuric  chloride.  The 
mercuric  chloride  precipitate  contained  a  base  the  quantity 
of  which,  however,  was  insufficient  for  a  complete  analysis 
(see  page  218).  The  mercuric  chloride  filtrate,  after  the 
removal  of  the  mercury  by  hydrogen  sulphide,  was  evapo- 
rated to  a  syrup,  and  this  was  then  repeatedly  extracted 
with  alcohol.  The  alcoholic  solution  thus  obtained  con- 
tained neuridiue,  a  base  of  the  same  composition  as  ethylene- 
diamine,  muscarine,  gadinine,  and  triethylamine.  These 
bases  were  separated  in  the  following  manner :  The 
alcoholic  solution  gave  with  platinum  chloride  a  precipitate 
of  ueuridine.  The  filtrate  from  this  platinum  precipitate 
was  heated  on  the  water-bath  to  expel  the  alcohol,  and  then 
the  platinum  was  removed  by  hydrogen  sulphide.  The 
aqueous  filtrate  was  concentrated  to  a  small  volume  which, 
on  addition  of  platinum  chloride,  gave  a  precipitate  of  the 
isomer  of  ethylenediamine.  The  mother-liquor  from  this 
precipitate  was  concentrated  on  a  water-bath,  and  on  cool- 
ing the  platinochloride  of  muscarine  crystallized  out.  From 
the  mother-liquor  of  this  precipitate  on  standing  in  a  des- 
iccator, the  gadinine  double  salt  crystallized.  The  mother- 
liquor  from  the  gadinine  platinochloride  was  treated  \vith 
hydrogen  sulphide  to  re'move  the  platinum,  and  the  aque- 
ous filtrate  on  distillation  with  potassium  hydrate  gave  tri- 
ethylamine. 

Gadinine  (from  Gadus  callarias,  haddock)  in  small 
doses  does  not  appear  to  be  poisonous ;  larger  doses 
(0.5-1  gram)  are  decidedly  toxic  and  may  kill  guinea- 
pigs.  The  formula  of  the  free  base  as  deduced  from  the 
analysis  of  the  platinochloride  may  be  either  C.Hj^NO.,  or 
C,H>0,.011. 

18 


206  PTOMAINES. 

The  Hyl>rochloeide,  Cj.HjyNO2.HCl,  as  obtained  by 
the  decomposition  of  the  platinochloride  with  hydrogen 
sulphide,  crystallizes  under  the  desiccator  in  thick  colorless 
needles,  which  are  easily  soluble  in  water;  insoluble  in 
alcohol.  It  forms  no  combination  with  gold  chloride,  but 
does  give  crystalline  precipitates  with  phosphomolybdic 
acid,  phosphotungstic  acid,  and  picric  acid. 

The  Platinochloride,  (C7Hi7NO.,HClXPtCl4  (Pt  = 
28  per  cent.),  is  at  first  quite  soluble,  and  on  standing  over 
a  desiccator  it  crystallizes  in  golden-yellow  plates,  which, 
when  once  formed,  are  again  difficultly  soluble  in  water. 
It  can  be  recrystallized  from  hot  water. 

Typhotoxine,  CjHjjNOj. — This  base  was  named  thus 
by  Beieger  (III.,  86),  and  is  regarded  by  him  as  the 
specific  toxic  product  of  the  activity  of  Koch-Eberth's 
typhoid  bacillus.  It  is,  however,  probable  that,  as  in  the 
case  of  tetanus,  there  are  other  basic  products  formed.  He 
obtained  it  by  cultivating  the  bacillus  on  beef-broth  for 
eight  to  fourteen  days  at  the  temperature  37.5°-38°.  The 
nature  of  the  soil  on  which  it  grows  has  a  great  deal  to  do 
with  the  formation  of  the  poison.  An  especially  important 
factor  is  the  temperature  :  for  Brieger  has  observed  that 
no  poison  was  produced  in  one  case  where  the  temperature 
remained  by  accident  at  39°  for  twenty-four  hours.  In 
such  cases  creatine  is  present  in  quantity,  whereas  otherwise 
the  reverse  is  the  rule. 

In  tlie  process  of  extraction  it  occurs  in  the  mercuric 
chloride  precipitate,  and  from  this  it  is  obtained,  after  the 
removal  of  the  mercury  by  hydrogen  sulphide,  as  an  easily 
deliquescent  hydrochroride.  This  for  the  purpose  of  puri- 
fication is  converted  into  the  difficultly  soluble  aurochloride. 

Typhotoxiue  is  isomeric  with  the  body  CyHj^NO,,  which 


TY  PIIOTOXINE.  207 

Brikger  obtained  Iroui  piitrclyini;'  Iiorsellesh.  In  its  ])!•()- 
perties  it  is,  iiowever,  very  dinereiit.  Tims,  the  free  base 
is  strongly  alkaline  and  its  hydrochloride  yields  a  difficultly 
soluble  picrate.  On  the  other  hand,  the  isomer  from  horse- 
flesh possesses  a  slightly  acid  reaction,  and  docw  not  form 
a  picrate.  Again,  typhotoxine  gives  with  Eiirijcii's  re- 
agent (sulplio-dia/obenzole)  an  immediate  yellow  color, 
whicii  disappears  upon  the  addition  of  alkali,  whereas  the 
isomer  does  not  give  this  reaction.  Furthermore,  the  two 
bases  differ  in  their  physiological  action  and  in  their  be- 
havior to  alkaloidal  reagents  (see  Table  I.).  Their  auro- 
chlorides,  however,  possess  the  same  melting-point. 

The  Hydrochloride  is  readily  deliquescent,  and  unites 
with  platinum  chloride  to  form  an  easily  soluble  double 
salt  crystallizing  in  needles. 

The  AuRociiLoiMDE,  CVHi^NCVHCLAuClj  (Au=40.45 
per  cent.),  is  dilHcultly  soluble,  and  crystallizes  in  prisms, 
which  melt  at  17(3°.  In  its  melting-point  and  solubility 
it  agrees  with  its  isomer  from  horseflesh.  From  some  of  his 
first  experiments  in  the  cultivation  of  the  typhoid  bacillus, 
Brieger  (II.,  69)  obtained  a  basic  product  differing  in 
some  of  its  characters  from  typhotoxine.  Its  aurochloride, 
on  analysis,  gave  41.91  and  41.97  per  cent,  of  Au;  1(5. 06 
per  cent,  of  C ;  and  3.66  per  cent,  of  H.,  whilst  typho- 
toxine aurochloride  gave  40.78  per  cent.  Au;  17.38  per 
cent.  C;  and  3.85  per  cent.  H.  For  a  comparison  of  the 
reaction  of  these  two  substances  see  Table  I. 

In  its  physiological  action,  typhotoxine  differs  from  its 
isomer  (page  209)  in  that  the  latter  produces  symptoms 
with  well-marked  convulsions,  whilst  the  former  throws 
the  animal  into  more  of  a  paralytic  or  lethargic  condition. 
The  action  of  this  base  has  been  studied  only  on  mice  and 
guinea-pigs.      It  produces  at  first  slight  salivation    with 


208  PTOMAINES. 

increased  respiration  ;  the  animals  lose  control  over  the 
muscles  of  the  trunk  and  extremities,  and  fall  down  help- 
less upon  their  sides.  The  pupils  become  strongly  dilated, 
and  cease  to  react  to  light ;  the  salivation  becomes  more 
profuse ;  the  rate  of  heart-beat  and  of  respiration  gradually 
decreases,  and  death  follows  in  from  one  to  two  days. 
Throughout  the  course  of  these  symptoms  the  animals  have 
frequent  diarrhceic  evacuations,  but  at  no  time  are  convul- 
sions present.  On  post-mortem,  the  heart  is  found  to  be 
contracted  in  systole,  the  lungs  are  strongly hyper8emic,the 
other  internal  organs  pale,  the  intestines  firmly  contracted, 
and  their  walls  pale. 

A  Base  (?)  O^H^yNOg  was  obtained  by  Beieger  (III., 

28)  on  working  over  about  one  hundred  pounds,  of  horse- 
flesh which  had  been  allowed  to  undergo  slow  putrefaction 
with  limited  access  of  air  and  at  a  low  temperature  ( — 9° 
to  +5°)  for  four  mouths.  It  occurs  in  the  mercuric 
chloride  precipitate  together  with  cadaverine,  putrescine, 
and  mydatoxine,  and  from  these  bases  it  can  be  separated 
and  isolated  according  to  the  method  on  page  200. 

The  free  substance  possesses,  even  after  most  careful 
purification,  a  slightly  acid  reaction.  This  acidity  is 
removed  from  even  a  large  quantity  of  the  substance  by 
the  addition  of  a  drop  of  alkali.  On  account  of  the  acid 
character  of  the  free  substance,  Beieger  does  not  consider 
it  to  be  a  base  (a  ptomaine).  It  differs,  however,  from  the 
amido-acids  in  its  poisonous  character;  in  the  fact  that, 
unlike  an  acid,  it  does  not  unite  with  bases  to  form  salts; 
and  in  not  giving  the  characteristic  red  coloration  (HoF- 
meistee'8  reaction  for  tjie  amido-acids)  with  ferric  chloride. 
Whatever  the  true  nature  of  this  substance  may  be,  it 
nevertheless,  in  its  other  properties,  behaves  like  a  base. 


BASK    (?)    C.Hi-NO.,.  209 

Thus,  it  forms  simple  as  well  as  tluuble  salts.  On  boiling 
with  copper  acetate,  it  gives  amorphous  flocctiles.  Under 
the  desiccator  it  solidifies  into  plates  which  deliquesce  on 
exposure  to  the  air.  It  docs  not  combine  either  with  silver 
oxide  or  with  cupric  hydrate.  On  dry  distillation  it  yields 
a  distillate  possessing  a  strong  acid  reaction  and  a  peculiar 
odor.  The  distillate  does  not  give  any  precipitate  M'ith 
platinum  chloride,  or  with  gold  chloride,  nor  does  it  react 
with  copper  acetate.  With  phosphomolybdic  acid,  how- 
ever, it  forms  an  amorphous  mass  ;  with  ferric  chloride  and 
potassium  ferricyanide  it  yields  an  immediate  precipitate  of 
Berlin-blue,  whereas  the  original  substance  does  not  give 
any  blue  coloration. 

The  Hydrochloride,  CyHj-NOo.HCl,  crystallizes  in 
tine  needles  which  are  insoluble  in  absolute  alcohol.  When 
its  aqueous  solution  is  treated  with  freshly  precipitated 
silver  oxide,  the  resulting  filtrate  contains  some  silver  oxide 
in  solution,  from  which  it  can  be  removed  by  hydrogen 
sulphide;  thus  dilfering  from  an  ammoniacal  silver  solu- 
tion, which  gives  no  precipitate  on  treatment  with  hydrogen 
sulphide.  In  this  respect  it  resembles  Salkoavski's  base, 
page  178.    For  reactions  of  the  hydrochloride,  see  Table  I. 

The  AuRocHLORiDE,  C-Hi^NO^.HCl.  AuClg  (Au= 
40.45  per  cent.),  forms  plates  which  are  difficultly  soluble 
in  water,  and  melt  at  176°.  It  is  dimorphous,  since  some- 
times it  is  also  obtained  in  needles  which  can  be  changed 
into  ])lates. 

Physiological  Action. — This  substance,  when  injected 
into  frogs,  produces  a  curara-like  action.  A  few  minutes 
after  the  injection  the  animal  falls  into  a  condition  of 
paralysis,  and,  although  it  can  still  react  toward  reflexes,  it 
cannot  move  from  its  place.  At  timeS' fibrillary  twitchings 
pass  over  the  body.     The  pupils  dilate,  the  heart-action 

18* 


210  PTOMAINES. 

becomes  gradually  weaker,  and  finally,  after  several  hours, 
the  animal  dies,  with  the  heart  in  diastole.  Doses  of  0.05 
to  0.3  gram  of  the  hydrochloride,  injected  into  guinea-pigs, 
produce  in  a  short  time  a  slight  tremor,  gradual  increase  in 
respiration,  and  slight  moistening  of  the  lower  lip.  The 
pupils  at  first  contract,  then  dilate  ad  maximum,  and  become 
reactionless.  The  temperature  remains  at  first  normal  ; 
chills  of  short  duration  follow  in  rapid  succession.  The 
animal  squats  on  the  ground  with  its  snout  pressing  against 
the  floor  in  exactly  similar  manner  as  is  caused  by  the 
mussel  poison.  Violent  clonic  convulsions  follow  in  con- 
tinually shorter  intervals,  and  at  the  same  time  lachryma- 
tion  and  salivation  become  profuse,  but  not  as  excessive 
as  in  the  case  of  the  muscarine-like  ptomaines.  The  tem- 
perature sinks  with  the  decrease  in  the  rate  of  respiration, 
the  ears  previously  gorged  become  pale  and  cold,  and  the 
heart-action  becomes  irregular  and  less  frequent  than  before. 
General  paralysis  sets  in,  but  the  head  still  moves  upward 
and  backward.  External  stimuli  induce  violent  clonic 
convulsions,  the  animal  repeats  frequently  choking  move- 
ments, and  at  the  same  time  yields  large  quantities  of 
saliva;  finally,  it  falls  upon  its  side  completely  paralyzed, 
and  dies.  The  heart  stops  in  diastole,  the  intestines  are 
pale  and  strongly  contracted,  and  the  bladder  is  empty  and 
likewise  contracted. 

A  Base  CgHjgNgO^  was  obtained  by  Pouchet  (1884) 
from  the  residual  liquors  resulting  from  an  industrial  treat- 
ment of  debris  of  bones,  flesh,  and  waste  of  all  kinds,  with 
dilute  sulphuric  acid.  It  is  accompanied  by  another  base, 
C^HjgNjOg,  from  which  it  can  be  separated  by  treatment 
with  alcohol.  The  base  itself  forms  tufts  of  delicate  needles 
which  alter  or  decompose  less  easily  than  the  accompanying 


TKTANINE.  211 

base.  The  platinocl.loritlc,  (Cyi,^N.p,.HClXPtCl„  forms 
a  dull  yellow  powder,  somewhat  soluble  in  strong  alcohol, 
but  insoluble  in  etiier. 

The  hydrochlorides  of  these  bases  form  silky  needles 
which  are  altered  by  excess  of  hydrochloric  acid  and  by 
exposure  to  air.  Pouchet  considers  them  to  be  closely 
allied  to  the  oxy-betaines.  The  general  alkaloidal  reagents 
precipitate  these  bases ;  the  phosphomolybdic  precipitate, 
on  addition  of  ammonia,  gives  a  blue  tint.  Both  bases  are 
toxic,  and  exert  a  paralyzing  action  upon  the  reflex  move- 
ments. 

The  method  employed  by  Pouchet  for  their  isolation 
was  to  precipitate  them  as  tannates.  The  precipitate  was 
decomposed  by  lead  hydrate  in  the  presence  of  strong 
alcohol,  the  excess  of  lead  removed  from  the  solution  by 
hydrogen  sulphide,  and  the  clear  liquid  thus  obtained  was 
submitted  to  dialysis.  The  above  bases  occurred  in  the 
dialysate. 

Tetaxixe,  CigHgoi^jC^j,  was  obtained  by  Brieoer  (III., 
94)  by  cultivating  impure  tetanus  microbes  of  Rosex^bach, 
in  an  atmosphere  of  hydrogen  on  beef-broth  for  eight  days 
at  37°-38°.  It  likewise  occurs  in  cultures  on  brain-broth. 
Quite  recently  (April,  1(S88),  Brieger  has  succeeded  in 
obtaining  tetanine  from  the  amputated  arm  of  a  tetanus 
patient,  identical  in  its  physiological  action  and  chemical 
reactions  with  that  isolated  from  cultures  of  Hosexbach's 
germs  on  beef-broth.  The  presence  of  tetanine  during  life 
in  tetanus  patients  has  thus  been  demonstrated.  It  has  not 
been  found  in  the  brain  and  nerve  tissue  of  persons  dead 
from  tetanus.  A  portion  of  the  jelly-like  mass  taken  from 
the  amputated  arm  was  found  to  contain  tetanus  bacilli  as 
well  as  staphylococci  and  streptococci,  and  when  ])lanted 


212  PTOMAINES. 

on  beef-broth,  tetaniue  was  formed,  but  no  tetanotoxiue  or 
sjjasmotoxine. 

For  its  isolation  Beiegee  employed  the  following 
method.  The  cultures  were  slightly  acidulated  with  hy- 
drochloric acid,  heated,  and  filtered ;  the  filtrate  was  then 
treated  with  lead  acetate  and  with  alcoholic  mercuric  chlo- 
ride in  the  manner  described  under  mytilotoxine  (page 
202).  The  filtrate  from  the  mercuric  chloride  precipitate 
contains  the  greater  part  of  the  active  principle,  provided 
the  precipitate  has  been  thoroughly  washed.  After  the  re- 
moval of  the  mercury  by  hydrogen  sulphide,  it  is  evapor- 
ated and  the  residue  is  repeatedly  extracted  with  absolute 
alcohol,  in  which  the  tetanus  poison  readily  dissolves,  and 
can  thus  be  separated  from  the  insoluble  ammonium 
chloride.  The  alcoholic  solution  is  treated  with  alcoholic 
platinum  chloride,  which  precipitates  the  ammonium  and 
creatinine  platinochlorides,  whilst  the  platinochloride  of  the 
poison  remains  in  solution.  The  filtrate  from  this  precipi- 
tate gives,  on  the  addition  of  ether,  a  flocculent  precipitate 
possessing  exceedingly  deliquescent  properties.  The  pre- 
cipitate is,  therefore,  rapidly  filtered  off  by  means  of  a 
pump,  and  dried  in  vacuum.  It  can  then  be  recrystallized 
from  hot  ninety-six  per  cent,  alcohol,  and  the  beautiful 
clear  yellow  plates  thus  obtained,  if  dried  again  in  vacuum, 
become  rather  difBcultly  soluble  in  water,  from  which  it 
can  then  be  recrystallized  and  obtained  in  a  perfectly  pure 
condition. 

Phosphomolybdic  acid  cannot  be  used  in  the  separation 
of  tetanine,  inasmuch  as  it  destroys  the  poison  (Beiegee). 
BocKLLSCH  has  also  observed  that  it  destroys  the  poison 
formed  in  the  putrefaction  of  fish. 

Tetanine  obtained  by  treating    the  hydrochloride  with 


TETANINE.  2l3 

freshly  precipitated  moist  silver  oxide,  forms  a  strongly 
alkaline  yellow  syrup.  With  alkaloidal  reagents  it  gives 
the  same  reactions  as  the  hydrochloride,  except  that  it  does 
not  give  a  blue  color  with  ferric  chloride  and  potassium 
ferricyanide.  It  is  easily  dccomposetl  in  acid  solution,  but 
is  permanent  in  alkaline  solution. 

The  Hydrochloride,  CjgHgyN.O^.SHCl,  is  deliques- 
cent and  is  easily  soluble  in  absolute  alcohol.  Besides  with 
platinum,  it  combines  only  with  phosphomolybdic  acid  to 
form  an  easily  soluble  crystalline  precipitate,  which  on  the 
addition  of  ammonium  hydrate  becomes  Avhite.  If,  how- 
ever, the  hydrochloride  is  impure,  phosphomolybdic  acid 
produces  a  precipitate  which  is  colored  an  intense  blue  by 
ammonia.  Potassium-bismuth  iodide  yields  a  ]>recipitate 
which  is  at  first  amorphous,  but  soon  becomes  crystalline. 
Ferric  chloride  and  potassium  ferricyanide  produce  a  slowly 
developing  blue  color  which  probably  is  due  to  impurities. 

The  Platixochloride,  C,3H3,N,0,.2HCl.PtCl,  (Pt  = 
28.65  per  cent.),  is  easily  soluble  in  absolute  alcohol  from 
which  it  is  precipitated  on  the  addition  of  ether.  From 
ninety-six  per  cent,  alcohol  it  crystallizes  in  clear  yellow 
plates.  After  repeated  recrystallization  from  alcohol  and 
drying  in  vacuum  it  becomes  difficultly  soluble  in  water  so 
that  it  can  be  recrystallized  from  the  latter.  It  decomposes 
at  197°. 

This  base  produces  the  characteristic,  though  probably 
not  all  the  symptoms  of  tetanus,  since  we  know  of  at  least 
three  other  toxines  (page  148)  which  occur  with  tetanine  in 
cultures  of  the  tetanus  microbe.  The  symptoms  induced 
by  relatively  large  doses  in  warm-blooded  animals,  as  mice, 
guinea-pigs,  and  rabbits,  exhibit  two  distinct  phases.  In 
the  first,  the  animal  is  thrown  into  a  lethargic  paralytic 
condition,  then  suddenly  becomes  uneasy,  and  the  respira- 


214-  PTOMAINES. 

tiou  becomes  more  frequent.  This  is  followed  by  the  second 
phase,  in  which  tonic  and  clonic  convulsions,  especially  the 
former,  predominate  till  death  results.  Small  doses  do  not 
seem  to  aifect  guiuea-pigs,  whilst  frogs  seem  to  be  much  less 
sensitive  than  mice.  The  characteristic  convulsions  and 
opisthotonus  seen  in  tetanus  in  man,  are  also  produced  in 
guiuea-pigs  on  injection  of  large  doses  of  this  base.  Dogs 
and  horses  seem  to  be  but  slightly  sensitive  to  the  action  of 
this  poison. 

A  Base  C^4N2uN204  was  isolated  by  Guaeeschi  from 
putrid  fibrin.  We  have  been  unable  to  obtain  any  descrip- 
tion of  this  compound. 

A  Base  C7HjgN206  was  isolated  by  Pouchet  in  1884, 
It  is  said  to  form  short,  thick  prisms  which  become  brown 
when  exposed  to  light. 

The  Platinochloeide,  (C7Hj8N,,06.HCl)2PtC]4,  crystal- 
lizes in  prismatic  needles  which  are  insoluble  in  strong 
alcohol.  For  further  details  in  regard  to  this  base  see 
page  210. 

Tyeotoxicon  has  been  obtained  in  poisonous  cheese 
(Vaughan,  Wallace,  Wolff),  in  poisonous  ice-cream 
(Vatjghax,  Novy,  Scheaeee,  Ladd),  in  poisonous 
milk  (Vaughax,  Novy,  Newtox,  AVallace,  Fieth, 
Schearee),  and  in  cream-puffs  (Staxtox).  The  methods 
of  separating  this  poison  and  its  effects  upon  animals  have 
already  been  given  with  sufficient  detail.  Chemically,  it  is 
very  unstable.  When  warmed  with  water  to  about  90°,  it 
decomposes.  Hydrogen  sulphide  also  decomposes  it,  there- 
fore all  attempts  to  isolate  it  by  precipitation  with  some 
base,  such  as  mercury  or  lead,  and  then  removing  the  base 


TYROTOXICON.  215 

with  hydrogen  sulphide,  have  failed.  Its  unstable  char- 
acter is  illustrated  bv  the  fact  that  it  may  disappear 
altogether  within  twenty-four  hours  from  milk  rich  in  the 
poison  which  is  allowed  to  stand  in  an  open  beaker. 

With  potassium  hydrate  it  forms  a  compound  which 
agrees  in  crystalline  form,  chemical  reactions,  and  the  per 
cent,  of  potassium  which  it  contains,  with  the  compound  of 
diazobenzole  and  potassium  hydrate.  This  substance  is  best 
obtained  from  milk  containing  tyrotoxicou  as  follows :  The 
filtered  milk,  which  is  acid  in  reaction,  is  neutralized  with 
sodium  carbonate,  agitated  with  an  equal  volume  of  ether, 
allowed  to  stand  in  a  stoppered  glass  cylinder  for  twenty- 
four  hours,  the  ether  removed,  and  allowed  to  evaporate 
spontaneously  from  an  open  dish.  The  acjueous  residue  is 
acidified  with  nitric  acid,  then  treated  with  an  equal  volume 
of  a  saturated  solution  of  potassium  hydrate,  and  the  whole 
concentrated  on  the  water-bath  (this  compound  is  not 
decomposed  below  130°).  On  being  heated  the  mixture 
becomes  yellowish-brown,  and  emits  a  peculiar  aromatic 
odor.  On  cooling  the  tyrotoxicon  compound  forms  in 
beautiful,  six-sided  plates  along  with  the  prisms  of  potas- 
sium nitrate. 

With  equal  parts  of  sulphuric  and  carbolic  acids,  pure 
tyrotoxicon  gives  a  green  coloration,  but  in  whey  the  color 
varies  from  yellow  to  orange-red.  This  color  reaction  may 
be  used  as  a  preliminary  test  in  examining  milk  for  tyro- 
toxicon. It  is  best  carried  out  as  follows  :  Place  on  a  clean 
porcelain  surface  two  or  three  drops  each  of  pure  carbolic 
and  sulphuric  acids.  Then  add  a  few  drops  of  the  aqueous 
solution  of  the  residue  left  after  the  spontaneous  evapora- 
tion of  the  ether.  If  tyrotoxicon  be  present,  a  yellow  to  an 
orange-red  coloration  will  be  produced.  This  test  is  to  be 
regarded  only  as  a  preliminary  one,  for  the  coloration  may 


216  PTOMAINES. 

be  due  to  the  presence  of  a  nitrate  or  nitrite.  The  tyro- 
toxicon  must  be  converted  into  the  potassium  compound 
and  purified  before  the  absence  of  nitrate  or  nitrite  can  be 
positively  demonstrated.  Moreover,  the  physiological  test 
should  always  be  made  in  testing  for  this  poison. 

With  platinum  chloride  in  alcoholic  solution  tyrotoxicon 
forms  a  compound  which  explodes  with  great  violence  at 
the  temperature  of  the  water-bath.  This  also  corresponds 
with  the  compound  of  platinum  chloride  and  diazobenzole. 

Pure  tyrotoxicon  is  insoluble  in  ether,  and  its  extraction 
from  alkaline  solutions  by  this  solvent  is  due  to  the  pres- 
ence of  foreign  matter,  with  which  the  poison  is  taken  up 
by  the  ether. 

The  physiological  action  of  this  ptomaine  has  been  suffi- 
ciently discussed  in  a  preceding  chapter. 

Mydaleine  (fivdaleog,  putrid)  is  a  poisonous  base 
obtained  from  putrefying  cadaveric  organs,  liver,  spleen, 
etc.  (Beiegee,  II.,  31,  48).  Though  it  is  apparently 
present  on  about  the  seventh  day,  it  is  unobtainable  until 
about  the  third  or  fourth  week.  The  method  for  its  sepa- 
ration from  the  accompanying  bases  is  given  under  saprine 
(page  109).  It  is  liable  to  occur  in  the  mercuric  chloride 
filtrate  as  well  as  in  the  precipitate,  inasmuch  as  the  double 
salt  is  insoluble  only  in  perfectly  absolute  alcohol.  In  order 
to  purify  the  platinochloride  as  obtained  on  page  169,  it  is 
repeatedly  recrystallized  from  a  very  small  quantity  of 
lukewarm  water.  This  base  has  not  been  obtained  in  suffi- 
cient quantity  to  permit  a  complete  determination  of  its 
composition.  It  is  probably  a  diamine,  containing  four  or 
five  carbon  atoms,  and  hence  is  nearly  related  to  some  of 
the  diamines  already  described. 

The  Platinochloeide,  on  analysis,  gave:  Pt=38.74, 


A  toxic'base.  217 

C=10.83,  H=3.23.  It  crystallizes  in  small  needles,  and 
is  extremely  soluble  in  water. 

The  Hydrochloride  crystallizes  with  extreme  diffi- 
culty, even  on  standing  for  some  time  in  a  desiccator.  On 
exposure  to  the  air  it  rapidly  deliquesces. 

Physiological  Action. — Mydaleiue  has  an  entirely 
specific  action.  Small  quantities  injected  into  guinea-pigs 
or  rabbits  produce,  after  a  short  time,  a  moistening  of  the 
under  lip,  and  an  abundant  flow  of  secretion  from  the  nose 
and  eyes.  The  pupils  dilate  gradually  to  maximum,  and 
become  reactionless ;  the  ear  vessels  become  strongly 
injected,  and  the  body  temperature  rises  1°  to  2°.  The 
hairs  bristle,  and  the  animal  occasionally  shudders.  Gradu- 
ally the  salivation  ceases,  the  respiration  and  heart- 
action,  which  were  at  first  hastened,  now  decrease,  the 
temperature  falls,  the  ears  become  pale,  and  the  animal 
finally  recovers.  During  the  action  of  the  poison  the 
animal  shows  a  tendency  to  sleep,  and  the  peristaltic  action 
of  the  intestines  is  heightened.  Larger  doses  (0.050  gram) 
induce  an  exceedingly  violent  action,  which  invariably 
results  in  the  death  of  the  animal.  On  post-mortem,  the 
heart  is  found  to  he  stopped  in  diastole,  and  the  intestines 
and  bladder  contracted :  otherwise  nothino;  abnormal  is 
observed. 

A  Toxic  Base. — From  human  livers  and  spleens  which 
were  decomposing  ibr  two  weeks  in  thorough  contact  with 
air  there  was  isolated,  besides  cadaverine  and  putrescine,  a 
small  quantity  of  a  poisonous  base  (Brieger,  II.,  29,  48). 
The  mercuric  chloride  precipitate  was  decomposed,  and  the 
hydrochlorides  were  precipitated  by  gold  cldoride(to  remove 
cadaverine,  which  is  soluble),  and  the  aurochloride  was  then 
changed    into  the   platinum  salt,  whereby   the   insoluble 

19 


218  PTOMAINES. 

putrescine  platiuochloride  was  removed.  In  the  mother- 
liquors  from  the  putrescine  salt  an  easily  soluble  platinum 
compound  was  separated,  and  found  to  contain  41.30  per 
cent.  Pt.  It  crystallized  in  fine  needles.  The  hydro- 
chloride forms  small,  readily  deliquescent  needles,  and  does 
not  produce  a  precipitate  in  alcoholic  platinum  chloride. 
Injected  into  guinea-pigs  and  rabbits  it  induced  an  exalted 
peristaltic  action  of  the  intestines,  which  lasted  several  days, 
and  produced  in  the  animals,  on  account  of  the  continuous 
evacuations,  a  condition  of  great  weakness.  No  disturb- 
ance in  the  functions  of  the  other  organs  was  observed. 

A  Base  was  isolated  from  decomposing  haddock  which 
were  exposed  for  five  days  during  summer  in  an  open  iron 
vessel.  Bkiegee  (I.,  42)  found  in  the  aqueous  mercuric 
chloride  precipitate  (see  page  205)  a  base  the  hydrochloride 
of  which  crystallized  in  well-formed,  small  needles.  The 
platiuochloride  likewise  crystallized  in  beautiful  needles, 
and  gave,  on  analysis,  36.03  per  cent,  of  Pt ;  7.81  per  cent. 
ofN. 

A  substance  of  muscarine-like  action  was  obtained  by 
Brieger  (I.,  59)  from  putrefying  gelatine,  ten  days  at  35°, 
though  in  insufficient  quantity  to  permit  a  determination 
of  its  character.  The  residue  containing  this  substance 
gave,  on  distillation  with  alkali,  only  ammonia. 

A  Base  was  obtained  by  Bocklisch  (III.,  52,  53)  from 
herring  which  had  undergone  putrefaction  for  twelve 
days.  It  was  found  in  tiie  distillate,  together  with  trime- 
thylamine  and  dimethylaraine,  obtained  by  distilling  the 
mercuric  chloride  filtrate,  after  the  removal  of  the  mercury, 
with    sodium   hydrate.       The   platiuochloride   was   easily 


UNDETERMINED    BASES.  219 

soluble,  aud  crystallized  in  large  thin  plates.  On  analysis, 
it  gave:  Pt=28.57,  C=22.34,  H=4.66.  The  hydro- 
chloride is  easily  soluble  in  water,  and  in  absolute  alcohol, 
and  besides  with  platinum  gives  only  with  phosphomolyl)- 
dic  acid  a  yellow  precipitate  which  is  soluble  in  excess,  and 
with  ammonia  gives  an  immediate  blue  color.  It  immedi- 
ately reduces  a  mixture  of  ferric  chloride  and  potassium 
ferricyauide  with  formation  of  Berlin  blue;  aud  similarly 
throws  down  metallic  gold  from  solutions  of  gold  chloride. 

From  poisonous  mussel,  Brieger  (III.,  79)  obtained  an 
aurochloride  of  a  base  crystallizing  in  needles.  The  quan- 
tity isolated  was  insufficient  for  analysis.  It  is  interesting 
because  of  its  property  of  inducing  salivation,  a  symptom 
which  has  been  observed  by  Schmidtmanx  and  by  Crumpe 
in  some  cases  of  mussel  poisoning. 

A  Base  was  obtained  by  Guareschi  and  Mosso  {Jouni. 
fib'  Praktische  Chcm.,  28,  508)  from  fresh  ox-flesh  in  the 
alkaline  ether  extract  obtained  by  Dragendorff's  method. 
It  formed  a  yellowish  alkaline  fluid,  of  unpleasant  odor, 
and  after  a  time  gave  a  deposit  of  microscopic  crystals. 
The  hydrochloride  gave  the  following  reactions :  Gold  chlo- 
ride, yellow  crystalline  precipitate  ;  platinum  chloride,  pre- 
cipitate; potassium  iodide  and  iodine  in  hydriodic  acid, 
kermes-red  precipitate ;  phosphotungstic  acid,  nothing ; 
phosphomolybdic  acid,  an  abundant  yellow  precipitate;  tan- 
nic acid,  heavy,  grayish  precipitate ;  same  with  jNIayer's 
reagent ;  picric  acid,  yellow  precipitate ;  Marme's  reagent, 
precipitate  soluble  in  excess  ;  })otassium  bichromate,  no- 
thing; potassium  permanganate  and  sulphuric  acid,  violet 
color  ;  potassium  ferricyauide  aud  ferric  chloride,  Prussian 
blue  precipitate. 


220  PTOMAINES 

By  giving  a  precipitate  with  tannin,  and  not  with  phos- 
photungstic  acid,  it  resembles  neurine. 

Ch.  Gram  has  studied  the  decomposition  of  yeast  under 
the  influence  of  an  infusion  of  hay.  The  yeast  was  allowed 
to  putrefy  for  fourteen  days,  and  was  then  treated  with  zinc 
sulphate.  The  latter  was  precipitated  by  barium  hydrate, 
and  the  filtrate,  after  the  removal  of  the  barium  by  sul- 
phuric acid,  was  evaporated  to  dryness,  and  extracted  with 
absolute  alcohol.  The  alcoholic  solution  was  evaporated, 
and  the  residue  again  extracted  with  alcohol.  The  extrac- 
tion residue  was  taken  up  with  water,  and  again  subjected 
to  the  above  treatment  with  zinc  sulphate,  barium  hydrate, 
etc. 

The  filtrate  was  poisonous,  and  produced,  in  frogs,  paral- 
ysis and  stoppage  of  the  heart  in  diastole.  Addition  of 
platinum  chloride  and  alcohol  precipitated  two  bases.  One 
of  these,  although  possessing  a  curara-like  action,  did  not 
affect  the  heart.  When  its  solution  was  heated  for  twenty- 
four  hours  on  the  water-bath,  it  caused  general  paralysis 
and  stoppage  of  the  heart.  The  platinochloride  contained 
38.05  per  cent,  of  platinum. 

The  other  base  also  possessed  a  slight  curara-like  action, 
and  its  platinochloride  gave,  on  analysis,  40.92  and  39.4 
per  cent,  of  platinum. 

Brieger  found  a  basic  substance  in  small  quantities  in 
cultures  of  the  staphylococcus  pyogenes  aureus  on  bouillon 
and  beef- broth  (II.,  74).  The  hydrochloride  formed  groups 
of  colorless,  non-deliquescent  needles.  With  platinum 
chloride  it  yielded  a  double  salt,  crystallizing  in  "needles, 
and  containing  32.93  per  cent,  of  Pt.  For  its  reactions,  see 
Table  I. 


UNDETERMINED    BASES.  221 

A  Base — boiling-point  about  284° — was  obtained  by 
Brieger  (II.,  61)  from  human  livers  and  spleens  which 
were  putrefying  for  two  to  three  weeks.  It  occurs  in  the 
mercuric  chloride  filtrate,  as  described  under  saprine,  page 
169,  together  with  some  mydaleine,  trimethylamine,  and 
hydrocarbons.  The  filtrate,  after  the  mercury  is  removed 
by  hydrogen  sulphide,  is  evaporated  to  dryness,  and  finally 
the  last  traces  of  water  are  removed  in  a  vacuum.  The 
residue  is  then  treated  with  absolute  alcohol,  and  from  this 
alcoholic  solution  the  mydaleine  is  precipitated  by  the  addi- 
tion of  alcoholic  mercuric  chloride.  The  trimethylamine 
is  separated  by  distillation  of  the  alkaline  filtrate,  previously 
deprived  of  its  mercury  by  hydrogen  sulphide ;  whilst  the 
mother-liquor  yields  an  oily  mixture  of  hydrocarbons  and 
bases.  The  latter  were  separated  by  fractional  distillation, 
whereby  only  one  of  the  bases  was  obtained  in  sufficient 
quantity  for  study.  It  boiled  at  about  284°,  and  gave, 
with  hydrochloric  acid  on  evaporation,  a  salt  crystallizing 
in  beautiful,  long  needles,  which  were  very  easily  soluble 
in  perfectly  absolute  alcohol.  With  gold  chloride  and  picric 
acid  it  gave  only  oily  products  ;  with  ferric  chloride  and 
potassium  ferricyanide,  an  intense  blue ;  with  platinum 
chloride,  an  extremely  easily  soluble  double  salt,  which 
appeared  under  the  microscope  in  the  form  of  very  fine 
needles,  whilst  from  alcohol-ether  the  double  salt  slowly 
separated  in  thin  plates  which  contained  30.36  per  cent,  of 
platinum.  The  free  base  shows  a  slight  fluorescence.  It 
is  not  poisonous,  and,  according  to  Brieger,  is  probably  a 
pyridine  derivative. 

Otiier  non-poisonous  bases  were  present  in  very  small 
quantity  in  the  mother-liquor  described  above,  after  the 

separation  of  the  oily  mixture. 

19* 


222  PTOMAINES 

Peptotoxine. — By  this  name  Briegee  (I.,  14-19)  has 
designated  a  poisonous  base  which  he  has  found  in  sonae 
peptones,  and  hence  in  the  digestion  of  fibrin  ;  in  putre- 
fying albuminous  substances,  such  as  fibrin,  casein,  brain, 
liver,  and  muscles.     It  is  a  well-known  fact  that  animal 
tissues,  in  the  early  stages  of  putrefaction,  possess  strong 
toxic  properties,  even  before  the  decomposition  could  have 
advanced  far  enough  to  effect  a  splitting-up  of  the  proteid 
and   carbohydrate  molecules.     Brieger  and    others  have 
tried  to  seek  an  explanation  of  this  toxicity  by  connecting 
it  with  an  early  peptonization  of  the  proteids  brought  about 
by  the  action  of  ferments  which  are  distributed  throughout 
the  tissues,  and  which  begin  their  activity  immediately  after 
death.     This  poison  has  not  been  definitely  isolated,  but  its 
general    properties    and    action    have    been    studied    by 
Brieger  and   Salkowski.     The  former  prepared  it  by 
digesting  fibrin  for  twenty-four  hours  with  gastric  juice  at 
the  temperature  of  the  blood.     The  perfectly  fresh  peptone 
thus  obtained  was  evaporated  to  a  syrupy  residue,  and  this 
was  then  extracted  Avith  boiling  alcohol.     The  residue  left 
on  evaporation  of  the  alcoholic  solution  was  digested  for 
some  time  with  amyl  alcohol,  which  on  subsequent  evapor- 
ation gave  amorphous  brownish  masses.     This  extract  can 
now  be  purified  by  neutral  lead  acetate.     The  filtrate,  after 
the  removal  of  the  lead  by  hydrogen  sulphide,  is  repeatedly 
extracted    with   ether,  then    evaporated    to   dryness,    and 
extracted  as  before,  with  amyl  alcohol.     This  final  extract 
is  evaporated  to  drive  off  the  alcohol,  taken  up  with  water, 
and  filtered.     The  colorless  aqueous  solution  thus  obtained 
contains  the  poisonous  substance,  which,  however,  can  only 
with   extreme  difficulty   be  brought    to  crystallization  in 
vacuum.  ' 

This  poison,  when  in  its  purest  condition,  as  shown  by 


I'EPTOTOXINE.  223 

its  failure  to  give  the  biuret  reaction,  possesses  a  neutral 
reaction.  Its  behavior  to  Millou's  reagent  is  quite  charac- 
teristic :  it  gives  a  white  precipitate,  which  on  boiling 
becomes  intensely  red.  From  this  reaction,  Br[EGER  is 
inclined  to  regard  this  substance  as  a  hydroxyl  or  an 
araido-derivative  of  benzole.  The  ptomaine  can  be  extracted 
from  acid  as  well  as  alkaline  solution  by  amyl  alcohol ; 
more  difficult,  in  the  cold,  than  on  heating.  It  is  abso- 
lutely insoluble  in  ether,  benzole,  and  chloroform ;  very 
soluble  in  water.  It  is  not  destroyed  by  boiling,  by 
passing  hydrogen  sulphide,  or  by  strong  alkalies;  but  is 
destroyed,  however,  when  the  putrefaction  lasts  longer 
than  eight  days.  For  its  behavior  to  reagents,  see  Table  I. 
Various  observers  have  shown  that  peptone  possesses  a 
toxic  action,  and  some  have  been  led  to  regard  this  toxicity 
as  not  due  to  the  peptone  itself  but  rather  to  the  presence 
of  this  or  some  other  ptomaine.  At  least  Briegp:r  found 
one  specimen  of  dry  Witte's  peptone  to  be  perfectly 
harmless ;  whereas,  the  fresh  peptone  formed  by  fibrin 
digestion  possessed  strong  toxic  powers.  Moreover,  this 
non-poisonous  peptone  when  exposed  to  the  action  of  gastric 
juice  was  found  to  yield  the  poisonous  substance.  The 
poisonous  nature  of  proteids,  and  the  physiological  action 
of  this  base  will  be  described  later. 


224 


PTOMAINES 
Table  of  Ptomaines. 


Formula 

Name. 

Discoverer. 

Physiological  action.^ 

C   H5  N 

Methylaniine. 

Dimethjiamine. 

Trimethylamine. 

Non-poisonous. 

Co  H-  X 

C3  Hg  N 

" 

Co  H;  N 

Ethylamine. 
Diethylamine. 

((                       (( 

C^  n'ns 

.. 

Ca  H,-X 

Triethylamine. 

11           11 

^0  ^-'lo^^ 

C3  H9  X 

Propylamine. 
AmylamiQe. 
Hexylamine. 
Tetanotoxino. 

C:;  HtiX 

^0    *^ld^' 

Ck  HisN 

C5  HiiN  (?) 

Brieger. 

Poisonous. 

CsHijN 

Collidine  {'!}. 

X'encki. 

Cs  H13X 

Itydrocollidine  ('!). 

Gautier  and  Etard . 

Poisonous. 

Cg  H^^^N 

Parvoline  (?). 

"        "        " 

C10HJ5N 

Unnamed. 

Guareschi  and  Mosso. 

Poisonous. 

Co  Hg  N2 

Ethylidenediamine  (?). 

Brieger. 

" 

C3  Hg  N2 

Trimethylenediamine. 

" 

C4  HjoNo 

Putrescine. 

" 

Non-poisonous. 

Co  H14N2 

Cadaverine. 

" 

"           " 

C3  H„N2 

Xeuridine. 

" 

"           " 

C5  H16N2 

Saprine. 

" 

" 

C-  H10N2 

Unnamed. 

MoriD. 

"           " 

C2  Hj  N3 

Methyl-guanidine. 

Brieger. 

" 

C13H20N4 

Unnamed. 

Oser. 

Cl7H3gN4 

" 

Gautier  and  Etard. 

Cg  H„N  0 

Mydine. 

Brieger. 

Non-poisonous. 

C5  H13N  0 

Neurine. 

" 

Poisonous. 

C5  HiiN  O2 

Unnamed 

B.  and  H.  Salkowski. 

Non-poisonous. 

Ci  H15X  O2 

Choline. 

Brieger. 

Poisonous. 

C5  Hi»X  O3 

Betaine. 

" 

Non-poisonous 

C5  H15N  O3 

Muscarine. 

" 

Poisonous. 

Ce  H13N  O2 

Mydatoxine. 

" 

*' 

Co  Hj5N  0„ 

Mytilutoxine 

" 

" 

C7  HnN  O2 

Gadinino. 

" 

Non-poisonous. 

Cj  HnN  O2 

Typhotoxine. 

" 

Poi-sonous. 

Cv  HijN  Oo 

Unnamed 

" 

" 

C5  HjoKoOo 

" 

Pouch  et. 

" 

C]  4^0^X004 

" 

Guareschi. 

C]3H3oXo04 

Tetanine 

Brieger. 

Poisonous. 

C,  H18X2O6 

Unnamed. 

Pouchet. 

" 

Tyrotoxicon. 

Yaughan. 

" 

Mydalelne. 

Brieger. 

" 

Spasmotoxine. 

" 

" 

Peptotoxine. 

1  Only  those  bases  are  here  denoted  as  poisonous  which  possess  a  decided  toxicity. 


CHAPTER    TIL 

CHEMISTRY  OF  THE  LEUCOMAINES. 

Under  this  head  are  classed  those  basic  substances  which 
are  found  in  the  living  tissues,  either  as  the  products  of 
fermentative  changes  or  of  retrograde  metamorphosis. 
Most  of  these  substances  have  already  been  known  for 
manv  vears,  though  their  real  sig-nificance  as  alkaloidal 
bodies,  and  their  relation  to  the  functional  activities  of  the 
animal  org-anism  have  been  but  little  understood,  or  rather 
thev  have  not  been  brought  together  under  the  leading 
conception  that  they  are  alkaloidal  products  of  physiologi- 
cal change.  The  first  attempt  at  the  systematic  study  and 
generalization  of  these  basic  substances  was  made  by 
Gautier,  who  applied  to  them  the  name  leucomaiues,  a 
term  derived  from  the  Greek  ?ei_xoua,  signifving  white  of 
eggs.  Under  this  name  he  includes  all  those  basic  sub- 
stances which  are  formed  in  animal  tissues  during  normal 
life,  in  contradistinction  to  the  ptomaines  or  basic  products 
of  putrefaction.  The  distinction  between  vegetable  and 
animal  alkaloids  is  not  very  well  defined,  and,  in  fact,  there 
seem  to  be  reasons  for  considering  their  formation  as  due 
to  the  same  causes  which  bear  an  intimate  relation  to  the 
physiology  of  the  cells  and  tissues  of  both  kingdoms. 
Thus,  vegetable  tissues  are  known  to  contain  not  onlv 
definite  ptomaines  such  as  choline,  but  also  leucomaines  as 
hypoxanthine,  xanthine,  etc.  Indeed,  in  this  latter  group 
must  be  placed,  on  account  of  their  relation  to  xanthine, 
those    well-defined   alkaloidal  bases,  caifeine  and  theobro- 


226  LEUCOMAINES 

mine.  Not  only  are  the  representatives  of  these  two 
divisions  of  basic  substances  common  to  botli  kingdoms, 
but  their  parent  bodies,  lecithin,  nucleiu,  etc.,  are  known 
to  occur  in  both,  thus  giving  rise  to  the  same  bases  on 
decomposition. 

So  far  as  the  genesis  of  most  of  the  leucomaines  is 
concerned,  we  know  very  little,  though  Gautier  is  of  the 
belief  that  they  are  being  formed  continuously  and 
incessantly  in  the  animal  tissues,  side  by  side  with  the 
formation  of  urea  and  carbonic  acid,  and  at  the  expense 
of  the  nitrogenous  elements.  Bouchard  has  sought  an 
explanation  of  the  presence  of  these  bases  in  the  urine,  by 
supposing  that  they  were  originally  formed  in  the  intestinal 
tract,  from  which  they  were  absorbed  into  the  system,  to  be 
subsequently  eliminated  by  the  kidneys.  This  view  has 
also  been  brought  forward  by  Schar  (1886),  who  holds 
that  these  bases,  which  may  be  formed  by  putrefactive 
fhauo;es  in  the  intestinal  tract,  are  absorbed  into  the  circu- 
latory  system,  whence  they  may  be  partly  eliminated 
by  the  kidneys  or  may  be  partly  deposited  in  the  tissues 
themselves. 

The  leucomaines  proper  can  be  divided  into  two  distinct 
and  well-defined  groups :  (1)  the  Uric  Acid  Group,  and 
(2)  the  Creatinine  Group. 

The  first  of  these  divisions  contains  a  number  of  well- 
known  bases  which  are  closely  related  to  uric  acid.  The 
order  in  which  they  will  be  described  is  as  follows  : 

Adenine,  C5H5N5. 

Hypoxanthine,  CgH^jST^O. 

Guanine,  C5H5N5O. 

Xanthine,  C^H.Np,. 

(Uric  Acid,  CgH.Npg.) 


LEUCOMAINES    OF    THE    URIC    ACID    GROUP.      227 

Heteroxauthiue,  C^HgX^O.^. 
Paraxanthine,  C^H^N^Oj. 
Carnine,  C-H3N,03. 

Pseudoxauthine,  C^H^Np. 
Spermine,  C^HjN. 

The  members  of  tlie  second  group  have  all  been  dis- 
covered by  Gautier,  and  by  him  are  regarded  as  allied 
to  creatine  and  creatinine.  These  two  substances,  especially 
the  latter,  have  been  hitherto  regarded  as  strongly  basic  in 
character,  but  Salkoavski  has  recently  shown  that  creati- 
nine, when  perfectly  pure,  possesses  little  or  no  alkaline 
reaction,  and,  moreover,  does  not  combine  with  acids.  The 
bases  in  this  group  are  : 

(Creatinine,  C.H^NgO.) 

(Creatine,  C.HgNgOg.) 

Cruso-creatinine,  CjHgN^O. 

Xautho-creatiuine,  C^Hj„N^O.  ■  ■ 

Amphi-creatine,  CglljgN^O^. 

Base,  CnH,,Ni„05. 

Base,  C\,H,,N,A- 

Besides  these  two  general  classes  of  leucoraaines,  there 
may  be  made  a  third  class  of  undetermined  leucomaines, 
embracing  those  bases  which  have  been  observed,  but 
studied  more  or  less  incompletely,  in  the  various  physio- 
logical secretions  of  the  body. 

Leucomaines  of  the  Uric  Acid  Group. 

Adenine,  C5H5N5,  which  has  been  recently  (1885) 
discovered  by  KoSvSEL,  forms  the  simplest  member  of  the 
uric  acid  group  of  leucomaines,  and  as  such  it  deserves 
special  attention,  inasmuch  as  it  shows  most  clearly  the 


228  LEUCOMAINES. 

relation  that  exists  between  hydrocyanic  acid  and  the 
members  of  this  group.  This  base  is  apparently  formed 
by  the  polymerization  of  hydrocyanic  acid,- — a  view  that  is 
confirmed,  at  least  in  part,  by  the  fact  that  on  heating  with 
potassium  hydrate  to  200°,  it  yields  a  large  quantity  of 
potassium  cyanide.  Moreover,  by  the  action  of  reducing 
agents  it  is  converted  into  a  substance  similar  to,  if  not 
identical  with  azulmic  acid.  It  has  not  been  prepared 
synthetically,  though  Gautier  has  claimed  to  have 
synthesized  two  closely  ^related  bodies,  xanthine  and  methyl- 
xanthine,  by  simple  heating  of  hydrocyanic  acid  in  a 
sealed  tube  in  contact  with  water  and  a  little  acetic  acid. 

This  base  was  first  prepared  from  pancreatic  glands — 
hence  the  term  adenine,  which  is  derived  from  the  Greek 
word  aSijv,  meaning  a  gland.  It  has  since  been  shown  to 
occur  together  with  guanine,  hypoxanthine,  etc.,  as  a 
decomposition-product  of  nuclein,  and,  therefore,  it  may 
be  obtained  from  all  tissues  and  organs,  animal  or  vege- 
table, rich  in  nucleated  cells.  Accordingly,  it  has  been 
found  in  the  kidneys,  spleen,  pancreatic  and  lymphatic 
glands,  in  beer -yeast,  and  tea -leaves.  In  the  latter, 
adenine  appears  to  exist  in  a  preformed  condition,  since  it 
can  be  extracted  without  the  use  of  acid  reagents.  It  has 
also  been  observed  in  the  liver  and  urine  of  leucocythseraic 
patients ;  its  occurrence  in  this  disease  will  be  readily 
understood  when  it  is  remembered  that  leucocythsemia  is 
characterized  by  the  presence  in  the  blood  of  an  unusual 
proportion  of  the  nucleated  white  blood  corpuscles,  which, 
owing  to  various  unfavorable  conditions  become  destroyed 
in  time,  and  the  contained  nuclein,  as  a  result,  splits  up 
into  adenine  and  guanine.  These  two  bases  may,  therefore, 
be  expected  in  all  pathological  conditions  where  there  is  an 
abnormal  accumulation  of  pus.     Indeed,  as  early  as  1865, 


LEUCOMAINES    OF    THE    URIC    ACID    GROUP.      229 

Naunyn  extracted  from  pius,  obtained  from  the  pleural 
cavity,  a  considerable  quantity  of  a  sub.stance  which 
probably  was  either  adenine  or  guanine,  or  both.  Adenine 
does  not  occur,  or  only  in  minute  traces,  in  meat  extract; 
and  in  this  it  resembles  guanine,  which  is  present  only  iu 
traces.  Kossel  explains  this  fact  on  the  ground  that  the 
muscle  tissue  is  very  poor  in  nucleated  cells,  i.  c,  in  nuclein. 
It  would  seem  that  the  muscle  cell  in  losing  the  morpho- 
logical character  of  a  cell  has  also  suffered  a  corresponding 
loss  in  its  chemical  properties.  For  while  the  decomposi- 
tion-products of  nuclein — hypoxanthine,  xanthine,  phos- 
phoric acid,  etc. — are  found  in  the  muscle  tissue,  they  do  not 
exist  in  combination  as  they  do  in  the  nuclein  molecule. 
This  is  seen  in  the  fact  that  the  bases  exist  in  the  free 
condition,  since  they  can  be  extracted  by  water ;  and  again, 
the  phosphoric  acid  is  present  in  the  muscle  tissue,  not  iu 
organic  combination,  but  as  a  salt.  In  the  nucleated  cell, 
adenine,  guanine,  etc.,  do  not  exist  in  the  free  condition  but 
form,  in  part  at  least,  with  albumen  and  phosphoric  acid, 
a  loose  combination  which  is  readily  decomposed  by  the 
action  of  acids  at  the  boiling  temperature.  This  same 
change  takes  place  spontaneously  after  death. 

There  can  be  no  doubt  that  adenine  and  guanine  play  an 
important  part  in  the  physiological  function  of  the  cell 
nucleus,  which,  from  recent  observations,  appears  to  be 
necessary  to  the  formation  and  building  up  of  organic 
matter.  It  is  now  known  that  non-nucleated  cells,  though 
capable  of  living,  are  not  capable  of  reproduction.  We 
must  look,  therefore,  to  the  nucleus  as  the  seat  of  the 
functional  activity  of  the  cell — indeed,  of  the  entire  organ- 
ism. Nuclein,  the  parent  substance  of  adenine  and  guanine, 
is  the  best  known,  and  probably  most  important  constituent 
of  the  nucleus,  and   as  such    it   has   been   already  credited 

20 


230  LEUCOMAINES, 

with  a  direct  relation  to  the  reproductive  powers  of  the 
cell.  This  chemical  view  has  recently  been  confirmed  by 
Zacharias,  who  showed  that  chromatin  of  histologists  is 
identical  with  nuclei n. 

The  method  employed  by  Kossel  for  the  preparation  of 
adenine,  is  as  follows :  The  finely  divided  pancreatic 
glands  are  heated  to  boiling,  for  three  to  four  hours,  with  a 
large  quantity  of  dilute  sulphuric  acid  (0.5  per  cent,  by 
volume  of  concentrated  acid),  and  the  acid  solution  thus 
obtained  is  treated  with  a  slight  excess  of  hot  concentrated 
baryta  water.  The  excess  of  baryta  is  removed  by  carbonic 
acid,  and  the  solution  is  then  filtered  ;  the  filtrate  is  con- 
centrated to  a  small  bulk,  about  100  c.  c,  rendered  alkaline 
with  ammonium  hydrate,  and  finally  precipitated  with  an 
ammoniacal  solution  of  silver  nitrate.  The  precipitate, 
consisting  of  the  silver  compounds  of  the  xanthine  bodies, 
is  partially  dried  by  spreading  over  porous  porcelain 
plates ;  then  dissolved  in  warm  nitric  acid  of  specific 
gravity  of  1.1,  to  which  a  little  urea  has  been  added  to 
prevent  the  formation  of  oxidation  or  nitro-products.  The 
filtered  acid  solution,  on  cooling,  gives  a  deposit  of  the 
silver  salts  of  hypoxanthine,  guanine,  and  adenine,  which 
is  filtered  off  and  thoroughly  washed.  The  filtrate  contains 
any  xanthine  silver  compound  that  may  be  present.  The 
washed  precipitate  of  the  silver  salts  is  suspended  in 
water,  decomposed  with  hydrogen  sulphide,  and  the  clear 
filtrate  is  concentrated  on  the  water  bath  to  a  small  volume. 
It  is  then  saturated  with  ammonium  hydrate  and  digested 
on  the  water  bath  for  some  time,  whereby  adenine  and 
hypoxanthine  go  into  solution,  whilst  the  guanine  remains 
undissolved.  From  the  ammoniacal  solution  on  partial 
concentration  and  subsequent  cooling,  the  adenine  crystal- 


LEUCOMAINES    OF    THE    URIC    ACID    GROUP.      2'61 

lizes  out  first,  whereas  the  more  sohihle  hyprjxanthine 
remains  in  sohition. 

Another  method  for  the  separation  of  adenine  from 
hypoxanthine  is  based  upon  the  behavior  of  the  nitrates  of 
these  bases  in  aqueous  sohition.  From  concentrated 
aqueous  solutions  of  the  nitrates,  free  liypoxauthine  crystal- 
lizes out  first,  because  the  nitrate  is  decomposed ;  whereas, 
adenine,  which  is  a  stronger  base,  remains  in  combination 
with  the  acid,  in  solution. 

Adenine,  when  crystallized  from  warm  or  impure  solu- 
tions, is  obtained  either  as  an  amorphous  substance,  or  in 
the  form  of  very  small  microscopic  needles  ;  from  dilute 
cold  solutions  it  separates  in  long,  needle-shaped  crystals 
containing  three  molecules  of  water.  This  water  of  crys- 
tallization is  lost  on  exposure  to  the  air  or  on  heating  to 
53°,  and  the  crystals  become  opaque.  It  is  soluble  in  about 
1086  parts  of  water  at  the  ordinary  temperature  ;  more 
easily  in  hot  water,  from  which,  on  cooling,  it  recrystallizes. 
The  aqueous  solution  possesses  a  neutral  reaction.  The 
free  base  is  insoluble  in  ether,  chloroform,  and  alcohol; 
soluble  in  glacial  acetic  acid,  and  somewhat  in  hot  alcohol. 
It  dissolves  readily  in  mineral  acids,  vieldino-  well-crvstal- 
lizable  salts.  The  fixed  alkalies  dissolved  it  with  ease,  but 
on  neutralization  of  the  solution  it  is  reprecipitated.  In 
aqueous  ammonium  hydrate  it  is  more  readily  soluble  than 
guanine,  and  more  difficultly  soluble  than  hypoxanthine — 
a  fact  which  is  made  use  of  to  effect  a  separation  from  these 
bases.     It  is  but  slightly  soluble  in  sodium  carbonate. 

Adenine  can  be  heated  to  278°  without  melting  ;  at  this 
temperature  it  becomes  slightly  yellow,  and  yields  a  white 
sublimate.  It  can  be  completely  volatilized  without  decom- 
position, by  heating  on  an  oil-bath  to  220°  ;  the  sublimate 
consists  of  pure,  white,  plumose  needles  of  adenine,  but  at 


232  LEUCOMAINES. 

250°  partial  decomposition  occurs,  and  some  hydrocyanic 
acid  forms.  When  heated  with  potassium  hydrate  to  200° 
on  an  oil-bath,  it  yields  a  considerable  quantity  of  potassium 
cyanide.  Adenine  is  quite  indifferent  to  the  action  of 
acids,  alkalies,  and  even  oxidizing  agents.  Thus,  it  may  be 
boiled  for  hours  with  baryta,  potash,  or  hydrochloric  acid, 
without  suffering  decomposition.  But  when  heated  with 
dilute  hydrochloric  acid,  or  concentrated  hydriodic  acid, 
in  a  sealed  tube  at  a  temperature  exceeding  100°,  adenine  is 
completely  decomposed,  with  formation  of  carbonic  acid 
and  ammonia  : 

C5H5Ng+5H,O  +  50=5CO,+5NH3. 

The  free  base,  as  well  as  benzoyl-adenine,  is  unaffected  by 
the  weak  oxidizing  action  of  potassium  permanganate,  but 
on  stronger  oxidation  it  is  wholly  destroyed.  Bromine  water 
produces  in  aqueous  solutions  of  adenine  an  oily  precipitate, 
which,  on  contact  with  potassium  hydrate  or  ammonia,  gives 
a  beautiful  red  or  violet  color.  Sodium  amalgam  and  zinc 
chloride  appear  to  have  no  action ;  but  on  boiling  with  zinc 
and  hydrochloric  acid  it  yields  a  very  unstable  reduction- 
product,  which  in  the  presence  of  oxygen  first  assumes  a  red 
color,  and  finally  throws  down  a  reddish-brown  precipitate. 
This  brown  substance  appears  to  be  identical  with  azulmic 
acid,  which  has  been  known  for  a  long  time  as  a  product  of 
the  polymerization  of  hydrocyanic  acid. 

When  adenine  is  evaporated  on  the  water-bath  with  dilute 
or  fuming  nitric  acid,  it  gives  a  white  residue  which  fails  to 
give  any  coloration  with  sodium  hydrate.  Similarly,  it 
does  not  give  the  so-called  Weidel'h  reaction  (murexide 
test)  on  evaporation  with  chlorine  water  and  exposure  of 
the  residue  to  an  ammoniacal  atmosphere.  In  this  respect 
it  resembles  hypoxanthine,   which,  when  pure,  does   not 


LEUCOMAINES    OF    THE    URIC    ACID    GROUP.       233 

answer  to  either  of  these  tests.  Another  test  for  adenine, 
which,  however,  is  given  also  by  hypoxanthiue  but  not  by 
guanine  and  caffeine,  is  as  follows  :  The  substance  to  be 
tested  is  digested  for  half  an  hour  with  zinc  and  hydro- 
chloric acid  in  a  test-tube  on  the  water-bath.  If  adenine  is 
present,  the  solution  will  assume  on  standing,  more  rapidly 
on  shaking,  a  ruby-red  coloration,  which  later  on  turns  into 
a  brownish-red.  This  reaction  depends  upon  the  formation 
of  a  reduction  product,  which,  owing  to  its  unstable  nature, 
is  soon  oxidized  by  the  oxygen  of  the  atmosphere  into  a 
brownish,  amorphous  substance,  apparently  identical  with 
azulmic  acid. 

On  treatment  with  nitrous  acid,  it  is  converted  into  hypo- 
xanthiue according  to  the  equation  : 

C,H,N,+HNO,=C,H,N,0  +  N,  +  H,0. 

This  formation  of  hypoxanthiue  from  adenine  is  analogous 
to  Strecker's  transformation  of  guanine  into  xanthine  by 
a  similar  action  of  nitrous  acid  (see  page  242).  In  both 
cases  the  change  of  a  highly  nitrogenized  body  into  a  less 
nitrogenized  body  is  accomplished  by  replacing  an  NH 
group  by  0,  or,  more  exactly,  of  an  XH^  group  by  OH. 
In  fact,  the  change  is  identical  with  that  seen  in  the  conver- 
sion of  primary  amines  into  primary  alcohols.     Thus, 

C,H5.NH,+HNO,=C,H50H-f-N,-fH,0. 

Ethvlamixe.  Ethtl  Alcohol. 

The  ease  with  which  adenine  and  guanine  are  reduced  out- 
side of  the  organism  shows  that  similar  changes  may  take 
place  within  the  cell-nucleus  proper.  For  Ave  know  that 
every  cell  is  endowed  with  an  enormous  reducing  power, 
and  hence  it  is  not  difficult  to  see  how  the  oxygen-free 
adenine  can  be  readily  converted  into  a  body  or  bodies 
which  greedily  take  up  oxygen.     We  must,  therefore,  look 

20* 


234  LEUCOMAINES. 

upon  adenine  and  guanine  not  only  as  the  antecedents  of 
hypoxanthine  and  xanthine,  but  also  as  intermediate  pro- 
ducts which,  when  they  form  in  the  cell,  may  give  rise  to 
important  chemical  processes,  especially  those  of  a  synthetic 
nature.  It  is  highly  probable  that  the  study  of  the  decom- 
position-products of  nuclein  will  explain  to  us  many  of  the 
metabolic  changes  in  the  organism,  and  throw  additional 
light  upon  the  migration  of  the  amido  group  from  the 
proteid  molecule  to  the  amido  acids  and  urea  derivatives. 
Thus,  the  formation  of  xanthine  from  guanine  represents 
the  conversion  of  a  guanidine  residue  into  a  urea  residue. 
A  similar  change  is  undoubtedly  effected  in  the  transform- 
ation of  adenine  into  hypoxanthine. 

Adenine  unites  with  bases,  acids,  and  salts.  The  salts  of 
adenine  with  mineral  acids  can  be  recrystallized,  thus 
differing  from  the  corresponding  salts  of  guanine  and  hypo- 
xanthine, which  are  dissociated  by  the  action  of  water. 
The  solutions  of  the  salts,  however,  possess  an  acid  reaction. 

The  hydrochloride,  CgHgNg.HCl-fJHjO,  forms  colorless, 
transparent,  strongly  refracting  crystals.  One  part  of  the 
anhydrous  salt  is  soluble  in  41.9  j)arts  of  cold  water. 

The  nitrate,  C5H5Ng.HN03  + JH^O,  crystallizes  from  the 
aqueous  solution  in  fine,  stellate  needles.  One  part  of  the 
dry  salt  dissolves  in  110.6  parts  of  water. 

The  sulphate,  {CJi.'N,),.}!^^ 0,-^211,0,  can  be  obtained 
from  the  aqueous  solution  in  two  different  crystalline  forms. 
It  is  easily  soluble  in  hot  water,  and  at  the  ordinary  tem- 
perature it  is  soluble  in  153  parts  of  water. 

The  oxalate,  C5H5N-.C,H,0,-f  H,0,  is  obtained  by  dis- 
solving adenine  in  hot,  dilute,  aqueous  oxalic  acid,  from 
which  solution,  on  cooling,  it  separates  as  a  voluminous, 
difficultly  soluble  precipitate  of  roundish  masses  which  are 
composed  of  long,  delicate  needles.    The  oxalates  of  guanine, 


LEUCOMAINES    OF    THK     URIC    ACID    GROUP.      235 

hypoxanthine,  and  xanthine  are  more  easily  soluble  than 
that  of  adenine,  and  exhil)it,  moreov^er,  a  different  appear- 
ance. 

The  platinochloride,  (C5H5N5.HCl),PtCI^,  crystallize-^ 
from  dilute  aqueous  solution  in  small  yellow  needles.  The 
concentrated  aqueous  solution  of  this  salt,  when  boiled  for 
some  time,  decomposes,  with  the  separation  of  a  clear, 
yellow  powder,  which  is  but  slightly  soluble  iuvcold  water, 
and  lias  the  composition  CgH^Nj.HCl.PtCl^. 

The  silver  salt  of  adenine,  CgH^N^Ag,  is  formed  when 
silver  nitrate  is  added  in  molecular  proportion  to  a  boiling 
ammoniacal  solution  of  adenine.  An  excess  of  silver 
nitrate  produces,  in  the  cold,  the  compound  CgH^Nj.Ag.O, 
which  is  converted  slowly  in  the  cold,  immediately  on 
warming,  into  the  other  salt  according  to  the  equation  : 

2C,n,X,.AgP  =  2C,H,X,Ag  +  AgP  +  H^O. 

Both  silver  compounds  are  difficultly  soluble  in  water 
and  ammonia.  Like  hypoxanthine  and  guanine  it  forms 
another  silver  salt  having  the  composition  C^H^Xg.AgXOj. 
It  is  obtained  by  dissolving  the  other  silver  compounds  in 
hot  nitric  acid ;  and  from  this  solution,  on  cooling,  it 
separates  in  needle-shaped  crystals  which,  however,  are  not 
permanent,  but  seem  constantly  to  give  off"  nitric  acid. 

Adenine,  when  treated  with  zinc  and  hydrochloric  acid 
in  the  cold,  forms  a  difficultly  soluble  crystalline  double 
salt  which  has  not  been  obtained  in  the  pure  state.  This 
double  salt  is  not  obtained  by  direct  treatment  of  adenine 
hydrochloride  with  zinc  chloride. 

One  of  the  hydrogen  atoms  of  adenine  is  capable  of 
rejilacement  by  organic  radicals.  Thus,  it  forms  crystalline 
methyl  and  ethyl  compounds. 

Acetyl-adenine,  C^H^Xj.CO.CHg,  can  be  obtained  In- 
heating   the    anhvdrous    base    with    an    excess    of  acetic 


236  LEUCOMAIXES. 

anhydride  for  some  time,  in  an  oil  bath,  at  130°.  It 
crystallizes  in  small  white  scales  which  dissolve  but  slightly 
in  cold  water  and  in  alcohol ;  more  readily  in  hot  water,  in 
dilute  acids  and  alkalies.  Heated  to  260°  it  becomes 
yellow  but  does  not  melt. 

Benzoyl-adenine,  CgH^Xg.CO.CgH,,  is  obtained  by  the 
action  of  benzoic  anhydride,  but  not  of  benzoyl  chloride, 
on  adenine.  It  cr^^stallizes  from  water  in  long,  lustrous, 
thin  needles  which  sometimes  are  grouped  in  bundles,  and 
melt  at  234°-235°.  It  is  easily  soluble  in  hot  alcohol,  from 
which  it  recrystallizes  on  cooling  ;  also  in  dilute  acids  and 
in  ammonia.  AVitn  atnnioniacal  silver  nitrate  it  gives  a 
precipitate  resembling  that  of  adenine,  but  is  more  readily 
soluble  in  ammonia.  This  compound  is  quite  stable,  since 
it  decomposes  very  slowly  on  boiling  with  hydrochloric 
acid  ;  on  protracted  boiling  with  water  it  is  changed  into 
adenine  and  benzoic  acid. 

Picric  acid  unites  with  adenine  to  form  an  easily  soluble 
compound.  The  aqueous  solution  of  the  base  is  precipitated 
by  baryta  water ;  alcoholic  zinc  chloride  also  yields  a  pre- 
cipitate which  is  soluble  in  excess  of  ammonium  hydrate. 
Mercurif^;  riiloride  produces  a  precipitate,  insoluble  in  hot 
water,  but  easily  soluljle  in  hydrochloric  acid.  Mercuric 
nitrate  also  gives  a  precipitate.  Cadmium  chloride  yields 
a  precipitate  which  dissolves  on  warming,  reappears  on 
coolincj,  and  is  solubl'^  in  ammonia.  Basic  lead  acetate  has 
no  effect 

Nothing  definite  is  known  in  regard  to  the  physiological 
action  of  adenine,  except  that  when  fed  to  dogs  it  appears 
to  be  eliminated  as  such,  in  part  at  least,  by  the  urine. 

Hypoxaxthixe,  C5H4N4O,  sometimes  also  known  as 
sarcine  or  sarkine,  was  discovered  by  Scherer  (1850)  in 


HYPOXANTHINE.  237 

splenic  pulp,  and  in  the  muscles  of  the  heart,  and  was 
named  thus  because  it  contains  one  atoni  of  oxygen  less 
than  xanthine.  It  has  since  been  obtained,  usually  accom- 
panying adenine  and  guanine,  from  nearly  all  of  the 
animal  tissues  and  organs  rich  in  nucleated  cells,  i.  c,  in 
nuclein.  It  has  been  found  in  blood*  after  death,  but  not 
in  blood  when  flowing  through  the  bloodv'essels.  Salomon 
has  recently  shown  it  to  be  a  normal  constituent  of  urine ; 
present,  however,  in  an  exceedingly  minute  quantity.  In 
the  blood  and  urine  of  leucocyth*mic  patients  it  occurs  in 
increased  quantity  owing  to  the  abnormally  large  number 
of  nucleated  white  blood  corpuscles  in  circulation  (see  page 
228),  Bence  Jones  observed  in  the  urine  of  a  boy,  who 
about  three  years  before  showed  the  symptoms  of  renal 
colic,  a  deposit  of  characteristic  whetstone-like  crystals 
resembling  uric  acid,  but  difl'ering  from  the  latter  by  dis- 
solving readily  on  the  application  of  heat,  whilst  from 
hydrochloric  acid  it  crystallized  in  elongated  six-sided 
plates.  These  crystals  he  considered  to  be  those  of 
xanthine,  but  Scherer  and  others  consider  them  to  be 
hypoxanthine.  It  is  therefore  quite  possible,  though  very 
rare,  for  this  base  to  form  a  deposit  in  the  urine  and  to  be 
confounded  in  shape  with  uric  acid.  Thudichum  has 
obtained  it  from  the  urine  of  persons  sick  with  liver  or 
kidney  diseases. 

Among  other  places  it  has  been  found  in  the  brain, 
muscle,  serum,  marrow  of  bones,  kidney,  heart,  spleen, 
liver,  peripheral  muscles ;  in  the  spawn  of  salmon 
(Piccard),  in  the  testicles  of  the  bull  (Salomon),  in  the 
nuclein  of  pus  and  red  corpuscles  (Kossel),  in  developing 
eggs,  and  in  putrefaction  of  albumen  (Salomon).  It  has 
also  been  found  in  the  spores  of  lycopodium,  and  in  the 
pollen  of  various  plants,  in  seed  of  black  pepper,  in  grass, 


238  LEUCOMAINES. 

clover,  oats,  bran  of  wheat,  larvae  of  ants;  in  the  jnice  of 
potato  (Schulze)  ;  in  certain  wines  (Kayser)  ;  in  the 
aqueous  decoction  of  yeast  of  beer  (Schutzenberger)  ;  and 
also  in  the  liquid  in  which  yeast  is  grown  (Bechamp). 
Demant  has  shown  it  to  be  relatively  abundant  in  the 
muscles  of  pigeons  in  a  state  of  inanition,  whilst  in  muscles 
of  well-fed  pigeons  it  is  said  to  be  entirely  absent. 
Salomon  found  hypoxanthine  and  xanthine  in  the  coty- 
ledons of  lupine,  as  well  as  in  the  sprouts  of  malt;  whilst 
Reinke  and  Rodewald  observed  these  two  bases  together 
with  guanine  in  ^thalium  septicum. 

Hypoxanthine  has  not  been  extracted  from  the  pancreas, 
where  it  seems  to  be  replaced  by  guanine,  or  rather  by 
adenine.  It  seems  that  hypoxanthine  bears  a  relation  to 
adenine  similar  to  that  which  we  see  between  glycocoll  and 
glycocolic  acid. 

Hypoxanthine  occurs  frequently  in  plants  together  with 
the  other  members  of  this  group,  namely,  adenine,  guanine, 
and  xanthine.  The  widely  distributed  character  of  these 
bases  is  due  to  the  presence  of  a  parent  substance,  viz., 
nuclein,  the  necessary  constituent  of  all  cells  capable  of 
development,  which  under  the  influence  of  acids,  and 
probably  likewise  of  ferments,  decomposes  into  the  above 
mentioned  bases.  They  may,  therefore,  be  considered  as 
the  first  steps  in  the  retrograde  metamorphosis  of  all 
tissues,  since  they  have  their  origin  in  nuclein,  an  impor- 
tant proteid  substance.  Recent  advances  in  biological 
chemistry  have  shown  that  the  undeveloped  eggs  of  various 
insects  and  birds  yield  much  less  quantity  of  xanthine 
bodies  (hypoxanthine,  xanthine,  etc.)  on  treatment  with 
dilute  acid  than  the  partially  developed  eggs  (Tichomiroff, 
Kossel).  This  is  dependent  upon  the  remarkable  fact 
observed    by    Kossel    that   the   nuclein    of  undeveloped 


HYPOXANTHINE.  239 

chicken  eggs  differs  from  the  micleiu  of  cell  nuclei  and 
resembles  that  obtained  from  milk.  For,  while  the  nuclein 
from  the  cell  nuclei  decomposes  into  adenine,  guanine, 
hypoxanthine,  etc.,  that  from  undeveloped  eggs  and  from 
milk  yields  no  nitrogenous  bases  on  treatment  with  acids. 
But  as  the  egg  develops,  i.  c,  the  nucleated  cells  increase  in 
number,  this  latter  nuclein  is  gradually  converted  or  gives 
way  to  the  ordinary  cell  nuclein,  and  hence  it  is  that  the 
chick  embryo  yields  guanine,  hypoxanthine,  and  possibly 
adenine. 

Unquestionably,  the  presence  of  hypoxanthine,  etc.,  in 
developing  cells  is  due  to  the  presence  of  tlie  nuclein  mole- 
cule from  which  it  is  readily  split  off.  In  muscle,  however, 
hypoxanthine  and  xanthine  appear  to  exist  preformed,  and 
bear  no  relation  to  nuclein,  since  they  are  in  the  free  condi- 
tion, and  can  be  extracted  from  the  tissue  by  water.  For 
an  explanation  of  this  peculiar  fact,  see  adenine,  page  229, 
and  guanine,  page  244. 

According  to  the  observations  of  Salomon  and  Chit- 
tenden, hypoxanthine  is  formed  by  the  digestion  of  blood 
fibrin  with  gastric  juice,  pancreatic  juice,  or  on  heating  with 
water  or  dilute  acids.  Egg  albumen  under  the  same  con- 
ditions does  not  yield  any  hypoxanthine,  except  when 
treated  with  pancreatic  juice.  These  observations  require 
repetition,  inasmuch  as  the  fibrin  used  undoubtedly  con- 
tained nuclein,  which,  as  we  now  know,  readily  decomposes 
under  those  conditions  into  its  characteristic  nitrog-enous 
bases.  Be  that  as  it  may,  it  appears,  however,  to  be  one 
of  the  products  formed  by  the  decomposition  and  successive 
oxidation  of  proteid  matter  previous  to  the  formation  of 
uric  acid  and  urea. 

When  a  mixture  of  guanine,  xanthine,  and  hypoxanthine 
is  allowed  to  putrefy,  the  bases  decompose  and  disappear  in 


240  LEIJCOMAINES. 

the  order  named.  Hypoxanthine  resists  bacterial  action 
the  longest,  and  this  corresponds  with  its  behavior  to  re- 
agents. 

Hypoxanthine  can  be  readily  obtained  from  a  number  of 
closely  related  substances.  Thus,  carnine,  by  the  action  of 
oxidizing  agents,  is  converted  into  hypoxanthine  (page  264). 
For  this  reason  Weidel  and  Schutzenberger  regard 
hypoxanthine  as  derived  from  carnine,  but  this  view  is  now 
entirely  set  aside  by  our  present  knowledge  of  the  relation 
of  this  base  to  nuclein. 

Again,  it  can  be  obtained  from  adenine  (page  233)  by  the 
action  of  nitrous  acid.  The  relation  that  hypoxanthine 
bears  to  uric  acid  is  shown  by  the  fact  that  the  latter  is 
converted  by  nascent  hydrogen  first  into  xanthine,  and 
finally  into  hypoxanthine. 

CJI AO3 + 2H  =  C,H  AO  +  2H,0. 

Uric  Acid. 

This  transformation  of  uric  acid  into  hypoxanthine  is  of 
especial  importance,  since  together  with  Horbaczewski's 
synthesis  of  uric  acid,  accomplished  by  acting  on  urea  with 
either  glycocoll  or  trichlorlactamide,  it  constitutes  the  last 
step  in  the  complete  synthesis  of  hypoxanthine  from  its 
elements. 

Hypoxanthine  has  been  hitherto  regarded  as  a  step  lower 
than  guanine  in  the  series  of  nitrogenous  products  of 
regressive  metamorphosis,  and  consequently  was  considered 
as  derived  from  guanine.  The  investigations  of  Kossel, 
however,  show  that  it  arises  not  from  guanine  but  from 
adenine.  On  the  other  hand,  guanine  is  to  be  looked  upon 
as  the  source  of  xanthine.  It  is  probable  that  in  the 
organism  it  is  oxidized  as  soon  as  it  is  set  free  from  the 
nuclein,  forming  successively  xanthine,  uric  acid,  urea,  etc., 
and  the  small  quantity  present  in  the  urine  is  all  that  has 


HYPOXANTHINE.  241 

escaped  oxidation.  When  fed  to  dogs,  it  was  observed  that 
the  amount  of  hypoxanthine  present  in  the  urine  decreased, 
and  even  became  less  in  amount  than  before  the  exjjeriment; 
but,  on  the  other  hand,  the  amount  of  xanthine  in  the  urine 
was  found  to  have  been  increased  above  the  normal.  This 
shows  that  hypoxanthine  in  the  body  is  oxidized  probably 
first  to  xanthine,  then  into  uric  acid.  According  to  Robert, 
hypoxanthine  is  a  true  muscle  stimulant. 

The  fact  that  hypoxanthine  is  so  widely  distributed  in 
the  organism,  and  in  much  larger  quantities  than  was 
formerly  supposed,  shows  that  it  constitutes,  together  with 
the  closely  related  bodies  creatine,  xanthine,  guanine,  etc., 
the  normal  antecedents  of  urea  and  uric  acid.  This  view 
is  furthermore  strengthened  since  hypoxanthine  is  especially 
abundant  in  those  organs  which  are  most  active  in  pro- 
ducing metabolic  changes  in  the  body,  viz.,  the  liver  and 
spleen. 

It  may  be  prepared  from  tlie  urine,  according  to  the 
method  given  under  paraxanthine  (page  258) ;  or  from 
extract  of  meat,  or  from  glandular  organs,  such  as  the  liver, 
spleen,  etc.,  by  the  process  on  page  230.  Nuclein,  on 
decomposition  with  acids,  yields  about  one  per  cent,  of  this 
base. 

Hypoxanthine  is  a  white,  colorless,  crystalline  powder, 
sometimes  in  part  amorphous,  soluble  in  about  300  parts 
of  cold  water.  It  is  more  easily  soluble  in  boiling  water 
(78  parts),  and,  on  cooling,  separates  in  the  form  of  white, 
crystalline  floccules,  thus  differing  from  xanthine,  which 
is  amorphous.  The  solubility  in  cold  alcohol  is  very 
slight,  about  1  to  1000.  It  dissolves  in  acids  and  alkalies 
without  decomposition,  and  from  solutions  in  the  latter  it 
can  be  precipitated  by  passing  carbonic  acid,  or  by  the 
addition  of  acetic  acid.     The  aqueous  solution  possesses  a 

21 


242  LEUCOMAINES. 

neutral  reactiou.  The  free  base  can  be  heated  up  to  150° 
without  suifering  decomposition,  but  above  this  temperature 
it  sublimes,  and  partially  decomposes,  with  evolution  of 
hydrocyanic  acid.  When  heated  with  potassium  hydrate 
to  200°,  it  yields  ammonia  and  potassium  cyanide.  Heated 
with  water  to  200°,  it  decomposes  into  carbonic  acid,  formic 
acid,  and  ammonia,  and  in  this  respect  it  agrees  with 
adenine  (page  232). 

When  evaporated  with  an  oxidizing  agent,  chlorine  water 
or  nitric  acid,  the  residue  is  said  to  give  on  contact  with 
ammonia  vapors  a  rose-red  color  (Weidel,  murexide  test). 
KossEL,'  however,  has  shown  that  this  is  due  to  the  presence 
of  xanthine,  and  that  pure  hypoxanthine  does  not  give  either 
the  murexide  test  or  the  xanthine  reaction.  According  to 
Steecker,  concentrated  nitric  acid  converts  hypoxanthine 
into  a  nitro-compound,  which  in  turn,  by  the  action  of  a 
reducing  agent,  is  changed  into  xanthine.  This  statement 
has  not  been  confirmed  either  by  Fischer  or  by  Kossel. 
It  does  not  give  a  green  color  with  sodium  hydrate  and 
chloride  of  lime — distinction  from  xanthine  (page  251). 

With  acids  it  yields  crystallizable  compounds,  and,  like 
the  amido  acids,  it  forms  compounds  with  bases,  and  also 
with  metallic  salts,  such  as  silver  nitrate  and  copper 
acetate. 

The  hydrochloride,  C5H,N,0.HC1  +  H,p,  crystallizes  in 
needles,  and,  like  the  nitrate  and  sulphate,  it  is  dissociated 
on  contact  with  water.  The  nitrate  forms  thick  prisms  or 
roundish  masses,  readily  soluble  in  water  and  ammonia. 
Platinum  chloride  forms  a  yellow,  crystalline  double  salt, 
having  the  composition  CgH^N^O.HCl.PtCl^. 

Phosphomolybdic  acid  precipitates  it  from  acid  solution, 
and  in  general  it  gives  the  ordinary  alkaloidal  reactions. 

It  is  not  precipitated   by  amraoniacal  basic  lead  acetate. 


GUANINE.  243 

Copper  acetate  does  not  precipitate  it  in  tlie  cold,  but  does 
on  boiling.  This  fact  has  been  made  use  of  in  the  isolation 
of  hypoxanthine.  Mercuric  chloride,  as  well  as  mercuric 
nitrate,  produces  a  flocculeut  precipitate. 

Altogether,  in  its  behavior  to  reagents,  it  resembles 
xanthine  to  a  very  considerable  degree.  The  two  can  be 
separated,  however,  by  the  ditferent  solubilities  of  the 
hydrochlorides  in  water,  and  more  especially  of  the  silver 
salt  in  nitric  acid.  Silver  nitrate  produces,  in  an  amraoni- 
acal  solution  of  these  bases,  a  precipitate  which  is  soluble  in 
hot  nitric  acid,  specific  gravity  1.1  ;  on  cooling,  the  hypo- 
xanthine silver  compound,  CjH^N^O.AgNOg,  crystallizes 
readily  in  the  form  of  tufts  of  microscopic  needles  or  plates, 
whereas  the  xanthine  compound  separates  very  slowly. 
From  the  ammoniacal  solution  hypoxanthine  is  precipitated 
by  silver  nitrate  as  C^H^N^O.AgjO,  corresponding  to  the 
xanthine  compound,  CgH^N^0.^.Ag20.  Like  adenine,  it 
probably  forms  another  silver  compound  in  ammoniacal 
solution,  having  the  composition  C5H3AgN40  +  H20. 

Guanine,  CgHgNgO,  was  discovered,  in  1844,  by  Unger, 
as  a  constituent  of  guano,  in  M'hich  it  is  present  in  varying 
quantities  according  to  the  region  from  which  the  guano 
comes.  Thus,  the  Peruvian  guano  is  reported  as  containing 
the  largest  proportion  of  this  base,  and  on  that  account  this 
variety  is  employed  when  it  is  desired  to  prepare  guanine. 
Since  its  discovery  by  Unger,  it  has  been  met  with  in  a 
very  large  number  of  tissues,  both  animal  and  vegetable; 
in  the  liver,  pancreas,  lungs,  retina,  and  in  the  testicle  sub- 
stance of  the  brdl ;  in  the  scales  of  the  bleak,  and  in  the 
swimming  bladder  of  fish,  as  well  as  in  the  excrements  of 
birds  and  insects.  It  is  also  found  in  the  spawn  and  testicle 
of  salmon,  and  Schueze  and  others  have  shown  it  to  be 


244  LEUCOMAINES. 

present  iu  the  young  leaves  of  the  plane-tree,  of  vine,  etc., 
also  in  grass,  clover,  oats,  as  well  as  in  the  pollen  of  various 
plants.  ScHUTZENBERGER  has  isolated  it,  together  with 
hypoxanthine,  xanthine,  and  caruine,  from  yeast  which  had 
been  allowed  to  stand  in  contact  with  water  at  near  the  body 
temperature.  Pathologically,  it  occurs  in  the  muscles, 
ligaments,  and  joints  of  swine  suffering  from  the  disease 
known  as  guauine-gout.  ISTormally,  guanine,  like  adenine, 
is  present  in  muscle  tissue  only  iu  traces.  It  has  never 
been  found  in  the  urine,  though  xanthine  has  been  mistaken 
for  guanine  by  some. 

As  to  the  origin  of  this  substance  in  the  organism  very 
little  has  been  known  up  to  within  a  few  years,  except  so 
far  as  it  has  been  shown  to  be,  together  with  other  members 
of  this  group,  a  transitory  product  in  the  retrograde  meta- 
morphosis of  nitrogenous  foods  and  tissues.  In  the  case  of 
the  lower  animals  it  is  evidently  the  end-product  of  all 
change,  inasmuch  as  it  is  excreted  as  such.  Our  knowledge 
as  to  the  immediate  origin  of  this  and  the  other  allied  bases 
has  lately  been  extended  by  the  brilliant  researches  of 
KossEL,  on  the  decomposition-products  of  nuclein,  in  which 
he  has  shown  that  this  essential  constituent  of  all  nucleated 
cells,  whether  animal  or  vegetable,  decomposes  under  the 
action  of  water  or  dilute  acids  into  adenine,  guanine,  hypo- 
xanthine,  and  xanthine.  We  know  that  the  first  two  bases 
are  readily  converted  by  the  action  of  nitrous  acid  into  the 
other  two ;  that  is  to  say,  an  NH  group  in  these  bases  is 
replaced  by  an  atom  of  O — a  change  which  it  is  not  at  all 
unlikely  takes  place  in  the  tissues,  perhaps  in  every  cell 
nucleus.  If  this  explanation  is  correct,  tlren  adenine  and 
guanine  are  transition-products  between  the  complex  proteid 
molecule  on  the  one  hand,  and  hypoxanthine  and  xanthine 
on  the  other.     These  two,  in  turn,  form  the  connecting  link 


GUANINE  245 

to  the  last  step  in  the  regressive  metamorphosis  of  the  nitro- 
genous elements  of  the  tissues,  viz.,  the  formation  of  uric 
acid  and  urea.  We  can  thus  trace  a  succession  of  cycles 
from  the  complex  nuclein  molecule,  which  is  apparently 
indispensable  to  the  functional  activity  of  all  reproductable 
cells,  to  the  physiologically  waste  products  urea  and  uric 
acid. 

ScHULZE  and  Bosshard  recently  (1886)  found  in  young 
vetch,  clover,  ergot,  etc.,  a  new  base,  to  which  they  have 
given  the  name  vernine.  It  has  the  formula  CigH2i,NgOg, 
and  is  of  especial  interest  at  this  point,  since  on  heating 
with  hydrochloric  acid  it  apparently  yields  guanine.  We 
have,  therefore,  at  least  two  well-defined  sources  of  guanine, 
the  nucleins  and  vernine. 

Neither  adenine  nor  guanine  occurs  in  normal  muscle 
further  than  in  mere  traces,  a  fact  which  can  only  be 
explained  on  the  ground  that  the  muscle  tissue  is  poor  in 
nucleated  cells,  and  hence  in  nucleiu.  Just  as  the  muscle 
cell  has  become  morphologically  differentiated  from  the 
typical  cell,  it  may  be  looked  upon  also  as  having  under- 
gone a  concomitant  chemical  differentiation,  inasmuch  as  we 
no  longer  find  the  phosphoric  acid,  xanthine,  and  hypo- 
xanthine  in  the  same  chemical  combination  as  they  occur  in 
the  original  cell.  The  phosphoric  acid,  instead  of  existing 
as  a  part  of  an  organic  compound,  is  present  in  the  muscle 
tissue  as  a  salt;  similarly  the  hypoxauthine  and  xanthine 
occur  in  the  free  condition,  extractable  by  water,  and  no 
longer  in  combination  with  other  groups  of  atoms  consti- 
tuting a  part  of  a  more  complex  molecule — nuclein. 

Guanine  and  creatine  apparently  mutually  replace  one 
another.  Thus,  in  the  nuiscle,  as  just  stated,  guanine  occurs 
only  in  traces,  whereas  creatine  is  especially  abundant. 
This  may  find  its  explanation  in  the  fact  that  both  are  sub- 

21* 


246  LEUCOMAINES. 

stituted  guanidines.  Creatine  is  regarded  by  Hoppe- 
Seylee  as  an  intermediate  product  in  the  formation  of 
urea,  and  a  similar  role,  it  will  be  remembered,  belongs  to 
guanine. 

In  the  decomposition  of  nuclein-containing  substances, 
such  as  yeast,  liver,  spleen,  etc.,  by  dilute  acids,  neither 
adenine  nor  guanine  is  found  alone,  but  they  are  always 
accompanied  by  hypoxanthine,  and  usually  by  a  very  small 
quantity  of  xanthine. 

Guanine  may  be  readily  prepared  from  Peruvian  guano 
by  boiling  it  repeatedly  with  milk  of  lime  until  the  liquid 
becomes  colorless.  The  residue,  consisting  largely  of  uric 
acid  and  guauine,  is  boiled  with  a  solution  of  sodium  car- 
bonate, filtered,  and  the  filtrate,  after  the  addition  of  sodium 
acetate,  is  strongly  acidulated  with  hydrochloric  acid.  This 
precipitates  the  guanine,  together  with  some  uric  acid.  The 
precipitate  is  dissolved  in  boiling  hydrochloric  acid,  and 
the  guanine  then  thrown  out  of  solution  by  the  addition  of 
ammonium  hydrate.  Guanine  is  also  obtained  in  the 
decomposition  of  nuclein  with  dilute  acids,  and  can,  there- 
fore, be  prepared  from  such  cellular  organs  as  the  spleen, 
pancreas,  etc,  according  to  the  method  given  on  page  230. 

The  free  base  forms  a  white,  amorphous  powder,  insol- 
uble in  water,  alcohol,  ether,  and  ammonium  hydrate ; 
easily  soluble  in  mineral  acids,  fixed  alkalies,  and  in  excess 
of  concentrated  ammonium  hydrate.  It  can  be  heated  to 
above  200°  without  undergoing  decomposition.  When 
evaporated  with  strong  nitric  acid  it  gives  a  yellow  residue, 
and  this  on  the  addition  of  sodium  hydrate  assumes  a  red 
color,  which  on  heating  becomes  purple.  This  is  the  so- 
called  xanthine  reaction,  and  is  supposed  to  be  due  to  the 
formation  of  xanthine  and  a  nitro  product.     It  is  given 


GUANINE.  247 

best  by  guanine,  then  by  xanthine,  and  is  not  given  by 
either  hypoxanthine  or  adenine. 

Nitrous  acid  converts  it  directly  into  xanthine.     Thus  : 

C,H,Np  +  HNO,  =  C,H,N  A  +  N,  +  H,0. 

This  reaction  is  identical  with  that  of  adenine,  whereby 
hypoxanthine  is  formed  (see  page  233).  On  oxidation  with 
potassium  permanganate  it  yields  urea,  oxalic  acid,  and  oxy- 
guanine.  By  hydrochloric  acid  and  potassium  chlorate  it 
is  oxidized  to  carbonic  acid,  guanidine,  and  parabanic  acid, 
according  to  the  equation  : 

CO-NH,  „  ^- 

CjHjNsO-f  11204-30=  I  )C0  +  ^2^  )C=NH+C02. 

CO— NH^  2^/ 

Parabanic  Acid.  Guanidine. 

According  to  Strecker,  a  small  amount  of  xanthine  is 
formed  in  this  reaction,  and  it  is  quite  possible  that  this 
base  is  also  formed  on  oxidation  with  nitric  acid. 

Guanine  combines  with  acids,  bases,  and  salts.  It  unites 
with  bases  to  form  crystalline  compounds ;  and  with  one  or 
two  equivalents  of  acids  it  also  yields  crystallizable  salts. 
Thus,  with  hydrochloric  acid  it  forms  the  two  salts, 
C5H5N,0.(HC1),  and  O^HgN.O.HCl  +  PI^O.  Similar  com- 
binations can  be  obtained  with  nitric  acid.  The  sulphate, 
(C5H5N50)2H2SO^,  crystallizes  in  long  needles,  and,  like 
the  other  salts,  is  decomposable  by  water.  The  platino- 
chloride,(C5H,NgO.HCl),PtCl,  +  2H20,  is  readily  obtained 
in  a  crystalline  condition.  The  silver  compound  is 
soluble  in  hot  nitric  acid,  and  on  cooling  recrystallizes 
in  fine,  needle-shaped  crystals  having  the  composition 
C,H,N,0.AgN03. 

The  solutions  of  the  hydrochloride  are  precipitated  by 
mercuric  chloride  and  nitrate,  potassium  chroraate,  potas- 
sium ferricyanide,  and  by  picric  acid.     Basic  lead  acetate 


248  LEUCOMAINES. 

gives  a  precipitate  only  on  addition  of  ammonium  hydrate. 
Tiie  reaction  with  picric  acid  (Caprantca)  is  said  to  be 
very  characteristic,  and  a  means  of  distinguishing  this  base 
from  xanthine  and  hj^oxanthine.  It  is  best  obtained  by 
adding  a  cold,  saturated  solution  of  picric  acid  to  the  warm, 
acidulated  solution  of  guanine,  when  a  light,  crystalline 
precipitate  forms.  Under  the  microscope  it  appears  in 
pencil-shaped,  fern-like  tufts  of  fine,  orange-yellow  needles. 

Xanthine,  CjH^N^Og,  is  also  very  widely  distributed  in 
the  organism,  and  has  been  met  with  in  almost  all  the 
tissues  and  liquids  of  the  animal  economy.  Together  with 
hypoxanthine,  guanine,  and  possibly  adenine,  it  occurs  in 
many  plants,  among  which  may  be  mentioned  lupine, 
sethalium,  sprouts  of  malt,  etc.  It  was  first  discovered  by 
Makcet  (1819)  in  a  urinary  calculus,  and  since  then  has 
been  frequently  found  as  the  only  or  chief  constituent  of 
many  calculi.  Unger  and  Phipson  have  extracted  it 
from  guano,  whilst  Salomon  has  shown  it  to  be  one  of  the 
products  formed  in  the  pancreatic  digestion  of  fibrin. 
Schutzenberger  found  it  together  with  carnine  and  hypo- 
xanthine in  the  liquors  from  yeast.  It  is  a  normal  con- 
stituent of  the  urine,  but  is  present  only  in  extremely 
minute  quantities.  During  the  use  of  sulphur-baths  or 
after  the  thorough  application  of  sulphur  salves  the  quan- 
tity of  xanthine  in  the  urine  is  considerably  increased.  It 
is  likewise  more  abundant  in  the  urine  of  leucocythsemic 
patients,  for  the  reasons  already  given  on  page  228. 
Baginski  holds  that  the  amount  of  xanthine  normally 
present  in  the  urine  may  be  increased  tenfold  in  the  case  of 
acute  nephritis.  Bence  Jones  observed  in  the  urine  of  a 
child  sick  with  renal  colic,  a  deposit  of  crystals  which  he 
considered  to  be  xanthine,  but  other  observers  are  inclined 


XANTHINE.  249 

to  regard  the  crystals  rather  as  hypoxanthiue.  Vaughan 
has  reported  the  presence  of  xanthine  in  deposits  from  the 
urine  of  patients  with  enlarged  spleen. 

Xanthine  may  be  prepared  synthetically  in  several  ways. 
Thus,  it  may  be  obtained  by  the  reduction  of  uric  acid  by 
means  of  sodium  amalgam,  according  to  the  equation  : 

C,H,N  A + H,=C,H,N  A  +  H,0. 

TJrk'Acid.  Xanthine. 

Now  that  uric  acid  has  been  prepared  .synthetically,  this 
forms  the  final  .step  in  the  complete  .synthesis  of  xanthine. 
By  further  action  of  nascent  hydrogen  the  xanthine  in  turn 
is  converted  into  hypoxanthiue.  It  is,  therefore,  evident 
that  these  bodies  form  a  continnous  oxidation  series  with 
uric  acid  as  the  final  product.  Although  this  change  is 
unquestionably  the  one  which  goes  on  in  the  animal 
economy,  yet  all  attempts  to  reproduce  it  in  the  laboratory 
by  oxidation  with  potassium  permanganate  or  nitric  acid 
have  apparently  yielded  only  negative  results.  Again, 
xanthine  may  be  prepared  from  guanine  by  oxidation  with 
nitrous  acid.  The  change  may  be  represented  by  this 
equation  : 

C,H,Np+HN0,=C,H,NA  +  N3+H,0. 

Guanine.  Xanthine. 

This  reaction,  first  described  by  Strecker  (1858),  corre- 
sponds exactly  to  the  one  by  which  Kossel  has  transformed 
adenine  into  hypoxanthiue  (see  page  233). 

Gautier,  starting  out  on  the  hypothesis  that  xanthine 
is  a  polymerization-product  of  hydrocyanic  acid,  has 
endeavored  to  prepare  it  directly  from  this  compound. 
Indeed,  he  claims  to  have  succeeded  in  effecting  the  .syn- 
thesis of  not  only  xanthine,  but  also  its  homologue,  by 
simply    heating   hydrocyanic  acid   in   a  sealed   tube    with 


250  LEUCOMAINES, 

water  and  a  little  acetic  acid  ;  the  latter  being  added  to 
neutralize  any  ammonia  that  might  form.  He  expresses 
the  reaction  as  follows  : 

1 IHCN  H-  4H,0=C,U,^p, + CgHgNp^ + 3NH3. 

Xanthine.         Methyl-xanthine. 

Nearly  all  of  the  methods  that  have  been  employed  for 
the  preparation  of  xanthine  are  based  upon  its  precipitation 
as  the  insoluble  silver  compound.  From  the  urine  it  can 
be  isolated  according  to  the  method  given  under  paraxan- 
thine^  on  page  258.  It  may  also  be  obtained  from  the 
urine  by  Hofmelster's  method.  The  urine,  acidulated 
with  hydrochloric  acid,  is  precipitated  with  phosphotungstic 
acid ;  the  precipitate  is  decomposed  by  warming  with 
baryta,  filtered,  and  the  filtrate  is  freed  from  barium  by  the 
cautious  addition  of  sulphuric  acid.  The  solution  is  then 
made  alkaline  with  ammonium  hydrate,  any  traces  of  phos- 
phates that  appear  are  filtered  off,  and  finally  it  is  precipi- 
tated by  addition  of  ammoniacal  silver  nitrate.  The  pre- 
cipitate which  forms  consists  of  the  silver  compounds  of  the 
xanthine  bodies,  and  is  purified  by  dissolving  in  hot  nitric 
acid,  as  given  on  page  230.  Xanthine  has  been  shown  to 
be  formed  at  the  same  time  with  guanine,  adenine,  and 
hypoxanthine,  in  the  decomposition  of  nuclein  by  means  of 
dilute  acids.  It  may,  therefore,  be  prepared  from  cellular 
organs  according  to  the  method  given  under  adenine. 

Xanthine  is  a  white,  granular,  amorphous  body,  and  is 
deposited  from  hot  aqueous  solution  on  cooling  in  colorless 
floccules,  or  as  a  fine  powder,  which,  under  the  microscope, 
is  seen  to  consist  of  rounded  granules.  When  occurring  in 
calculi,  it  forms  compact,  moderately  hard,  yellow  or  brown 
fragments,  which,  on  being  rubbed  with  the  finger-nail, 
assume  a  wax-like  appearance.  It  is  difficultly  soluble  in 
cold  water  (about  14,000  parts),  alcohol,  and  ether ;  some- 


XANTHINE,  251 

what  more  soluble  iu  boiling'  water  (about  120U  pai't«).  It 
is  soluble  in  alkalies  and  alkali  carbonates,  not  bicarbon- 
ate, and  from  these  solutions  it  is  precipitated  on  neutrali- 
zation with  acids,  or  by  passing  carbonic  acid.  In  warm 
ammonia  it  dissolves  more  readily  than  does  uric  acid  or 
guanine,  and  on  cooling  the  ammonium  compound  recrys- 
tallizes.  It  acts  as  a  weak  base,  and  as  a  weak  acid ;  with 
salts  of  the  heavy  metals  it  forms  difficultly  soluble  or 
insoluble  compounds.  Its  basic  properties,  however,  are 
weaker  than  those  of  hypoxauthine  or  guanine. 

When  xanthine  is  evaporated  with  nitric  acid  it  leaves  a 
lemon-yellow  residue  (hence  its  name),  which  is  not  changed 
by  ammonium  hydrate — distinction  from  uric  acid — but 
with  potassium  hydrate  becomes  yellowish-red,  on  heating 
purple-red.  When  added  to  a  mixture  of  bleaching  powder 
and  sodium  hydrate  in  a  watch-glass  the  solution  becomes 
covered  by  a  dark-green  scum,  which  changes  to  a  brown, 
and  soon  disappears — distinction  from  hypoxanthine. 

By  means  of  a  very  interesting  synthetic  reaction,  xan- 
thine may  be  converted  into  theobromine,  the  active  con- 
stituent of  Theobroma  cacao.  Thus,  the  xanthine  is  dissolved 
in  a  sufficient  cjuantity  of  sodium  hydrate,  necessary  to  form 
the  neutral  compound  CgHgNagN^Og,  and  this  product, 
when  treated  with  boiling  acetate  of  lead,  yields  a  white 
precipitate  of  lead  xanthine,  C5H2PbN^02.  This  is  dried 
at  130°,  then  heated  for  twelve  hours  at  100°  with  methyl 
iodide,  when  the  dimethyl  derivative,  C5H2(CH3)2i^^02,  is 
formed.  This  compound  is  identical  with  the  natural  theo- 
bromine, and  by  a  similar  treatment  is  converted  into  tri- 
methyl-xanthine  or  caffi^ine.  The  relation  of  xanthine  to 
theine  (caffeine)  is  shown  iu  the  fact  that  it  exists  together 
with  hypoxanthine,  adenine,  and  possibly  guanine,  in  fresh 
tea-leaves.     It  is,  therefore,  clear  that  by  starting  from 


252  LEUCOMAINES. 

guanine  of  guano  we  can  produce  successively  xanthine, 
dimethyl  xanthine,  and  trimethyl  xanthine,  the  last  two 
compounds  being  identical  with  the  alkaloids  of  theobroma 
and  of  coffee. 

Nascent  hydrogen  converts  this  base  into  hypoxanthine, 
but  the  reverse  operation,  the  oxidation  of  hypoxanthine 
into  xanthine,  has  been  questioned  of  late  by  Kossel  and 
others.  On  heating,  a  small  portion  volatilizes ;  the 
greater  part  decomposes  into  ammonium  carbonate,  cya- 
nogen, and  hydrocyanic  acid.  Heated  to  200°  with  hydro- 
chloric acid,  it  decomposes  with  the  formation  of  ammonia, 
carbonic  acid,  formic  acid,  and  glycocoU  (E.  Schmidt). 
When  bromine  is  allowed  to  act  on  xanthine,  there  is 
formed  a  substitution  compound,  having  the  formula 
C5H3BrN402.  With  potassium  chlorate  and  hydrochloric 
acid  it  yields  alloxan  and  urea. 

Xanthine  is  a  weak  base,  which  dissolves  in  acids  with 
the  formation  of  salts. 

The  hydrochloride,  CgH.NA-HCl,  is  difficultly  soluble 
in  water,  more  so  than  the  corresponding  salt  of  hypoxan- 
thine, from  which  it  is  deposited  in  glistening  six-sided 
plates,  often  forming  aggregations.  Its  solution  does  not 
precipitate  platinum  chloride.  The  nitrate  forms  fine  yellow 
crystals. 

The  sulphate,  CgH^NPg-HaSO^  +  H2O,  crystallizes  in 
microscopic  glistening  rhombic  plates,  decomposable  by 
water. 

With  baryta  water,  xanthine  forms  the  difficultly  soluble 
compound  C5H4N402.Ba(OH)2,  which  corresponds  to  the 
hypoxanthine  salt  CJIJ^JD.B-d{0Il)2,  and  to  that  of 
guanine. 

From  ammoniacal  solution,  silver  nitrate  precipitates  the 
compound  CgH^N^Og.  AggO,  which  is  insoluble  in  ammonia, 
but  soluble  in  hot  nitric  acid.     From  the  nitric  acid  solu- 


XANTHINE.  253 

tiou,  on  long  standing,  tliere  separates  the  compound 
C5H^Nj02.AgN03,  whicli,  on  contact  with  water,  decom- 
poses, giving  off  nitric  acid.  The  ammoniacal  solution  is 
also  precipitated  by  lead  acetate — separation  from  hypo- 
xanthine — also  by  calcium  and  zinc  chlorides.  Cupric 
acetate  gives  a  precipitate  only  on  boiling.  The  aqueous 
solution  is  not  precipitated  by  lead  acetate,  but  is  by  phos- 
phomolybdic  acid,  phosphotungstic  acid,  by  mercurous  and 
mercuric  salts.  Picric  acid  gives  an  easily  soluble  com- 
pound, which  resembles  that  of  hypoxanthine,  but  differs 
from  that  of  guanine. 

As  to  the  physiological  relation  of  xanthine  very  little 
need  be  said.  It  bears  the  same  relation  to  o;uanine  that 
hypoxanthine  does  to  adenine,  and,  like  the  latter,  is  to  be 
looked  upon  as  an  intermediate  compound,  a  step  lower 
than  guanine,  and  nearer  the  limit  of  oxidation — uric  acid. 
It  is  quite  probable  that  in  the  body  it  is  oxidized  about 
as  rapidly  as  it  is  formed.  Like  hypoxanthine,  it  is  to 
be  regarded  as  a  true  muscle  stimulant,  especially  of  the 
heart.     (Baginski.) 

In  closing  the  description  of  the  preceding  bodies  it  may 
be  well  to  present  briefly  our  present  knowledge  as  to  tiieir 
constitution.  Gautier,  starting  out  with  the  idea  that 
they  are  polymerization-products  of  hydrocyanic  acid,  has 
deduced  theoretically  cyclic  formulae,  recalling  the  hexagon 
of  the  benzole  derivatives.  These  formukie,  though  formid- 
able in  appearance,  are  a  complete  failure  so  far  as  they  are 
expressions  of  chemical  reactions.  Thus,  the  formula  of 
guanine : 

N=CII 
H— CO— nC  \C=NH 

HN  NH 

22 


254 


LEUCOMAINES. 


fails  to  show  either  a  urea  or  a  guanidine  residue,  and  yet 
it  is  a  well-kuowu  fact  that  guanine  on  oxidation  yields 
parabanic  acid  and  guanidine  (page  247).  In  a  similar 
manner,  his  xanthine  formula  fails  to  show  up  the  urea 
residues  which  we  know  to  be  present. 

HoRBACZEWSKi's  Synthesis  of  uric  acid  has  thrown  con- 
siderable light  upon  the  constitution  of  these  bases.  As  a 
consequence  of  his  method  of  synthesis  uric  acid  was  shown 
to  possess  the  structural  formula  given  below.  E.  Fischer 
has  found,  as  a  result  of  experimental  work,  the  constitu- 
tion of  xanthine  to  be  expressed  by  the  subjoined  formula. 
We  know  that  uric  acid  on  treatment  with  nascent  hydro- 
gen is  couverted  into  xanthine,  then  into  hypoxanthiue. 
It  follows,  therefore,  that  a  relation  exists  between  hypo- 
xanthiue and  xanthine  similar  to  that  between  xanthine 
and  uric  acid.  The  formula  of  hypoxanthiue,  as  deduced 
from  this  relation,  and  given  below,  probably  represents 
its  constitution  quite  closely.  It  is  possible,  however,  that 
the  CH  and  CO  groups  will  be  found  to  occupy  the 
reverse  position  which  they  are  given  in  this  formula,  in 
which  case  corresponding  changes  must  be  made  in  the 
formulae  of  guanine  and  adenine.  The  latter  two  are 
based  upon  the  relation  which  these  bodies  bear  to  xanthine 
and  hypoxanthiue,  and  cannot  be  said  to  be  the  result  of 
direct  experimental  evidence. 

NH— C  —  NH       N  ==  C  —  NH        N=C  —  NH 


CO 

NH— C       CO 


CO 

NH— 0       CO 


CH 

N— 0        CO 


CO— NH 

Ukic  Acid. 

C,H,NA 


CH— NH 


Xanthine. 

C,H,N,0, 


CH— NH 

Hypoxanthine. 

C,H,Np 


HETEROXANTHINE 


255 


N  =  C  —  NH 


N=C 


NH 


CO 

I 
NH— C 


C=NH 


on 

II 

N— 0       C=NH 


CH— NH 

Guanine. 

C.H.N.O 


CH— NH 


C.H.N. 


Heteroxanthine,  CgHgN^O^,  is  a  new  base  which  was 
isolated  from  the  urine  in  1884  by  Salomox.  In  its 
composition  it  is  methyl-xauthine,  and  is  intermediate 
between  xanthine  and  paraxanthine  or  dimethyl-xanthine. 
It  occurs  in  the  urine  of  man  and  of  the  dog  in  about 
the  same  amount  as  paraxanthine,  and  the  method  for 
its  isolation  will  be  found  under  the  description  of  that 
base.  It  is  a  remarkable  fact  tiiat  this  base  occurs  in 
dog's  urine  unaccompanied  by  paraxanthine,  and  the  same 
seems  to  hold  true  for  the  urine  of  leucocythaemic  persons. 
Salomon  examined  the  liver  and  muscles  of  a  dog,  but 
was  unable  to  obtain  any  heteroxanthine  or  paraxanthine, 
and  the  total  amount  of  xanthine  bodies  present  was 
about  normal.  Hence,  he  is  inclined  to  think  that  these 
two  bases  may  possibly  have  their  origin  in  the  kidney. 
Unlike  the  other  xanthine  bodies,  heteroxanthine  has  not 
as  yet  been  isolated  from  plants,  meat  extract,  or  guano. 
The  amount  of  xanthine  bodies  present  in  the  urine  is 
unaffected  by  phosphorus  poisoning.  Neither  this  base  nor 
paraxanthine  has  been  found  in  bull's  testicles ;  xanthine 
is  also  absent,  and  only  hypoxanthine  and  guanine  were 
found  to  be  present. 

Heteroxanthine  forms  a  white  amorphous  powder 
which  sometimes  on  prolonged  contact  with  water  forms 
microscopic  crystalline  tufts.     It  is  very  difficultly  soluble 


256  LEUCOMAINES. 

in  cold  water ;  much  more  easily  iu  hot  water,  and  the 
solution  thus  obtained  is  neutral  iu  reaction.  It  is  easily 
soluble  in  ammonium  hydrate,  but  is  insoluble  in  alcohol 
and  ether.  When  heated  it  volatilizes  without  melting  and 
at  the  same  time  gives  off  a  small  quantity  of  hydrocyanic 
acid.  On  evaporation  with  nitric  acid  on  the  water  bath 
(xanthine  reaction)  it  remains  as  a  pure  white  residue, 
which  on  contact  with  sodium  hydrate  develops  only  a 
trace  of  reddish  coloration  or  none  at  all.  Weidel's 
test  (page  264)  produces  a  splendid  red  color  which 
becomes  blue  on  the  addition  of  sodium  hydrate.  Simple 
evaporation  with  chlorine  water  gives  a  similar,  though 
not  so  strong  a  color  reaction. 

Silver  nitrate  produces  in  ammoniacal,  as  well  as  in 
nitric  acid  solutions,  a  precipitate  which  dissolves  on 
warming  readily  in  even  very  dilute  nitric  acid  ;  from  this 
solution,  if  not  too  concentrated,  the  heteroxanthine  silver 
nitrate  compound  crystallizes  in  well-formed  plate-like 
prismatic  crystals.  Copper  acetate  produces  in  the  cold,  in 
solutions  of  heteroxanthine,  a  clear-green  precipitate.  It 
is  also  precipitated  by  phosphotungstic  acid,  and  by 
ammoniacal  basic  lead  acetate.  Picric  acid  does  not  give 
a  yellow  colored  precipitate  in  solutions  of  the  hydrochlo- 
ride. Mercuric  chloride  readily  precipitates  heteroxanthine 
in  the  form  of  a  grayish-yellow  compound,  which  on 
standing  twelve  to  twenty-four  hours  becomes  converted 
into  pure  white  crystalline  aggregations.  This  mercuric 
compound  can  be  converted  directly  into  the  corresponding 
silver  compound  by  the  addition  of  silver  nitrate  and 
ammonia,  as  described  under  paraxanthine. 

The  hydrochloride  is  characterized  by  its  rather  difficult 
solubility  and  ready  crystallization  (a  distinction  from  the 
paraxanthine   salt).     The  salt   forms   large  colorless   tufts 


HETEROXANTHINE.  257 

of  crystals,  which  on  contact  with  water  soon  lose  their 
transparency  and  become  opaque ;  gradually  their  crystal- 
line form  disappears,  till  finally  they  completely  decompose 
with  the  formation  of  heteroxanthiue.  This  decomposition 
is  hastened  by  warming,  either  with  or  without  addition  of 
ammonia.  Platinum  chloride  produces  in  the  hydrochloric 
acid  solution  a  precipitate  of  a  crystalline  double  salt. 

This  base  resembles  paraxanthine  in  its  property  of 
yielding  a  difficultly  soluble  precipitate  with  the  fixed 
alkali.  This  reaction  is  best  brought  about  by  dissolving 
the  heteroxanthine  hydrochloride  in  warm  dilute  sodium 
hydrate,  when,  on  cooling,  the  corresponding  sodium  salt 
will  crystallize  out  in  oblique  angle  plates.  These  crystals 
dissolve  easily  in  water,  and  on  neutralization  of  the 
solution  with  an  acid  a  dense  pulverulent  precipitate  of 
heteroxanthine  forms.  It  can  thus  be  distiuguished  from 
paraxanthine,  the  sodium  compound  of  which,  on  similar 
treatment,  yields  the  characteristic  crystalline  form  of  the 
free  base.  This  sodium  reaction,  therefore,  distinguishes  it 
at  once  from  xanthine,  hypoxanthine,  guanine,  and  para- 
xanthine. It  differs  from  the  latter,  as  has  already  been 
indicated,  in  the  solubility  and  amorphous  character  of  the 
free  base;  in  the  behavior  of  the  hydrochloride  and  the 
sodium  compound,  and  in  the  not  giving  a  precipitate  with 
picric  acid,  nor  the  characteristic  odor  given  by  paraxan- 
thine on  heating. 

In  its  composition,  heteroxanthine  is,  as  has  already 
been  stated,  methyl-xauthine  and  probably  is  related  to  if 
not  identical  with  an  isomeric  body  obtained  synthetically 
by  Gautier  (see  page  249).  The  fact  nevertheless 
remains,  that  in  the  urine  we  have  normally  a  homologous 
series  of  xanthine  bodies,  namely,  xanthine,  hetero- 
xanthine, and  paraxanthine. 

22* 


258  LEUCOMAINES, 

Paraxanthine,  C^HgN^Og,  was  isolated  in  1883  by 
Salomon,  who  has  since  shown  it  to  be  a  constituent  of 
normal  urine,  although  present  in  exceedingly  minute 
quantity.  Thus  from  1200  litres  of  urine,  only  1.2  grams 
(0.0001  per  cent.)  of  this  substance  were  obtained.  It  has 
not  been  found  in  the  urine  of  dogs  or  in  that  of  leucocy- 
thsemic  patients,  Thudichum  was  the  first  to  isolate 
paraxanthine  from  the  urine,  and  he  named  it  urotheo- 
bromine  (1879). 

The  method  employed  for  the  isolation  of  this  base  is, 
with  a  slight  modification,  that  of  E.  Salkowski,  as 
originally  proposed  for  the  preparation  of  the  xanthine 
bases  from  urine.  The  urine  in  portions  of  25  to  50 
litres  is  made  alkaline  with  ammonium  hydrate  and 
allowed  to  stand  twenty-four  hours.  The  clear  super- 
natant fluid  is  decanted  from  the  precipitate  of  phos- 
phates and  treated  with  silver  nitrate  (0.5  to  0.6  gram 
per  litre).  The  grayish  precipitate  of  xanthine  compounds 
which  forms  is  transferred  to  a  filter  and  washed  with 
water  till  free  from  chlorides  ;  it  is  then  suspended  in 
water  and  decomposed  with  a  current  of  hydrogen 
sulphide.  The  liquid  is  filtered  by  decantation  and  the 
filtrate  is  evaporated  to  dryness ;  the  residue  is  extracted 
with  three  per  cent,  sulphuric  acid  to  remove  uric  acid  ; 
the  solution  thus  obtained,  after  it  has  been  rendered  alka- 
line with  ammonia,  is  precipitated  by  silver  nitrate. 

A  better  procedure  is  to  concentrate  the  filtrate  directly 
over  the  flame  or  on  the  water  bath,  till  the  uric  acid  begins 
to  crystallize  out.  It  is  then  filtered,  and  the  filtrate,  after 
diluting  somewhat  with  water,  is  rendered  alkaline  with 
ammonium  hydrate  in  order  to  precipitate  any  remaining 
uric  acid  and  phosphates.  The  whole  is  allowed  to  stand 
one  or  two  days,  then  filtered,  and  the   filtrate  again   pre- 


PARAXANTHINE.  259 

cipitated  with  silver  nitrate.  The  thoroughly  washed 
precipitate  of  the  xanthine  compounds  now  obtained,  free 
from  uric  acid,  is  dissolved  in  as  little  as  possible  of  hot 
nitric  acid  of  specific  gravity  1.1,  to  which  a  little  urea 
has  been  added,  and  the  clear  solution  is  set  aside  for 
twenty-four  hours.  The  silver  salt  of  hypoxanthine 
crystallizes  from  the  solution  and  is  filtered  off.  It  can  be 
purified  by  repeated  recrystallization  from  hot  nitric  acid 
containing  a  little  urea,  then  decomposed  with  hydrogen 
sulphide,  and  the  filtrate,  rendered  alkaline  with  ammonium 
hydrate,  is  concentrated  to  a  small  volume.  On  standing, 
pure  hypoxanthine  crystallizes  out.  The  filtrate  from  the 
silver  salt  of  hypoxanthine  on  being  rendered  alkaline 
with  ammonium  hydrate  gives  a  precipitate  which  formerly 
was  rey-arded  as  consistins;  entirely  of  the  xanthine  silver 
compound,  but  which,  from  the  investigations  of  Salomon, 
has  been  shown  to  be  a  mixture  of  the  salts  of  xanthine, 
paraxanthinc,  and  heteroxanthine. 

The  separation  of  these  bases  is  effected  by  the  solubility 
of  the  free  bases  in  ammonium  hydrate.  For  this  purpose 
the  precipitate  of  the  mixed  silver  salts  is  decomposed  with 
hydrogen  sulphide,  and  the  filtrate  is  rendered  amraoniacal 
to  remove  traces  of  phosphates  and  oxalates,  and  moderately 
concentrated.  After  standing  twenty-four  hours,  heteroxan- 
thine crystallizes  out,  partly  in  finely  formed  sheaves  and 
tufts  of  needles,  partly  in  radially  striated  masses.  The 
fluid  is  decanted  from  the  crust  of  heteroxanthine  which 
forms  in  the  bottom  of  the  beaker  and  after  being  con- 
centrated somewhat  is  again  allowed  to  stand.  In  this  way 
a  second  crop  is  ol)tained,  and  this  is  repeated  till  finally 
the  separated  masses  scarcely  give  a  precipitate  with 
sodium  hydrate.  All  the  heteroxanthine  is  now  united 
and  dissolved  in  a  little  hot  Mater  by  the  aid  of  sodium 


260  LEUCOMAINES. 

hydrate.  After  twenty-four  hours  the  greater  part  of  the 
heteroxanthiue  crystallizes  out  in  bunches  of  crystals  of 
sodium  heteroxanthine,  whilst  a  small  part  together  with 
any  traces  of  xanthine  remains  in  solution.  The  crystalline 
mass  is  dried  by  pressure,  dissolved  in  a  little  water,  and 
the  solution  neutralized  by  addition  of  hydrochloric  acid, 
when  the  heteroxanthine  separates  as  a  pulverulent  pre- 
cipitate. To  remove  any  traces  of  paraxanthine,  dissolve 
iu  hydrochloric  acid;  on  standing  forty-eight  hours  the 
heteroxanthine  salt  separates,  whilst  the  easily  soluble  salt 
of  paraxanthine  remains  in  solution.  To  obtain  the  pure 
free  heteroxanthine,  the  hydrochloric  salt  is  evaporated 
with  ammonium  hydrate ;  the  well-washed  residue  of 
heteroxanthiue  is  then  dissolved  in  dilute  ammonia,  the 
solution  filtered,  evaporated  slowly,  and  the  precipitate 
which  forms  is  finally  washed  with  alcohol  and  ether. 

The  original  ammouiacal  mother -liquors  of  hetero- 
xanthiue yield  on  further  concentration  amorphous  floc- 
cules  of  xanthine,  which  are  removed  by  filtration ;  and 
from  the  filtrate,  when  concentrated  still  more,  para- 
xanthine crystallizes  out. 

Paraxanthine  is  obtained  in  colorless,  glassy,  generally 
six-sided  plates,  which  are  arranged  in  tufts  or  rosettes. 
From  very  concentrated  aqueous  solutions  it  crystallizes  iu 
long,  colorless,  interwoven  needles,  which  on  drying  exhibit 
the  silky  lustre  of  tyrosin.  The  crystals  belong  to  the 
monoclinic  system,  and  do  not  contain  any  water  of  crys- 
tallization. It  can  be  heated  to  250°  without  melting  or 
suffering  any  decomposition,  but  when  heated  more  strongly 
it  gives  off  white  vapors  which  possess  a  distinct  iso-nitril 
odor,  at  the  same  time  it  carbonizes  and  takes  fire.  When 
evaporated  with  concentrated  nitric  acid,  as  iu  the  ordinary 
xanthine  test,  it  gives  only  a  slight  yellow  residue.  On 
the  other  hand,  Weidel's  test,  evaporation  with  chlorine 


PARAXANTHINE.  261 

water  containing  a  trace  of  nitric  acid,  and  then  i)lacing 
the  dry  residue  into  an  ainnioniacal  atmosphere  under  a 
bell-jar,  gives  a  beautiful  rose-red  color. 

It  is  difficultly  soluble  in  cold  water  (though  more  easily 
than  xanthine) ;  somewhat  more  readily  soluble  in  hot 
water,  and  insoluble  in  ether  and  alcohol.  It  is  soluble  in 
ammonium  hydrate,  hydrochloric  acid,  and  nitric  acid. 
Its  solutions  react  neutral. 

Silver  nitrate  produces  in  nitric  acid,  as  well  as  in 
ammoniacal  solutions,  a  flocculent  or  gelatinous  precipitate, 
which  in  concentrated  solutions  forms  an  almost  perfect 
jelly-like  mass.  This  silver  precipitate  is  soluble  in  warm 
nitric  acid,  from  which  on  cooling  it  separates  in  white 
crystalline  tufts  possessing  a  silky  lustre.  On  decomposi- 
tion with  hydrogen  sulphide  the  silver  salt  yields  pure 
paraxauthine.  Picric  acid  produces  in  the  hydrochloric 
acid  solution  a  precipitate  consisting  of  densely  felted 
yellow  crystalline  spangles. 

It  is  also  precipitated  by  phosphotuugstic  acid  and  copper 
acetate ;  mercuric  chloride  when  added  in  excess  gives  a 
precipitate  composed  of  a  mass  of  colorless  prisms,  which 
are  rather  difficultly  soluble  in  cold  water;  easily  in  hot 
water.  The  crystals  of  paraxauthine  mercuric  chloride 
when  moderately  heated  become  opaque  from  loss  of  water 
of  crystallization  ;  at  a  higher  temperature  they  melt,  under- 
going at  the  same  time  partial  decomposition,  and  on  strong 
heating  they  evolve  disagreeable  nauseating  vapors.  The 
aqueous  solution  of  this  mercuric  double  salt  gives  with 
silver  nitrate  an  abundant  precipitate  of  silver  chloride, 
which  disappears  on  the  addition  of  ammonium  hydrate 
and  is  replaced  by  the  flocculent  gelatinous  precipitate  of 
silver  paraxauthine.  The  hydrochloric  acid  solution  of 
paraxauthine  crystallizes  with  difficulty  even  when  strongly 
concentrated,  and  on  the  addition  of  platinum  chloride  it 


262  LEUCOMAINES. 

yields  a  well-crystallizable  orauge  colored  paraxanthine 
platinochloride.  It  is  not  precipitated  by  basic  lead  acetate 
nor  by  mercuric  nitrate. 

In  its  behavior  to  the  xanthine  test  this  base  resembles 
hypoxanthine,  whereas  in  giving  Weidel's  reaction  it 
approaches  xanthine.  Finally,  it  coincides  with  guanine 
by  yielding  a  precipitate  with  picric  acid.  Although  it 
thus  agrees  in  some  of  its  reactions  M'ith  all  three  of  these 
xanthine  bodies,  it  can,  however,  be  easily  distinguished 
from  them  by  its  behavior  with  the  fixed  alkalies.  Sodium 
or  potassium  hydrate  dissolves  these  bases  and  holds  them 
in  solution,  but  when  added  to  concentrated  paraxanthine 
solution  the  alkali  produces  a  precipitate  of  long,  glittering, 
crystalline  spangles,  which  under  the  microscope  are  seen  to 
consist  of  delicate  rectangular,  often  longitudinally  striated, 
plates  which  are  either  isolated  or  united  in  tufts.  Besides 
these  crystals  there  are  also  present  hexagonal  plates  re- 
sembling cystin.  The  crystals  are  soluble  in  a  little  water, 
or  on  warming,  but  precipitate  again  on  cooling.  Para- 
xanthine, however,  shares  with  heteroxanthine  the  property 
of  forming  a  difficultly  soluble  compound  with  the  fixed  alka- 
lies, but  can  be  distinguished  from  the  latter  by  neutraliz- 
ing with  an  acid  the  solutiou  of  the  sodium  or  potassium 
compound,  when,  in  the  case  of  paraxanthine,  there  will  be 
obtained  a  precipitate  of  the  characteristic  crystals  of  that 
base ;  whereas  heteroxanthine  is  obtained  on  similar  treat- 
ment as  a  dense  pulverulent  precipitate. 

It  is  interesting  to  observe  that  paraxanthine  is  isomeric 
with  theobromine,  and  also  with  a  body  recently  described 
by  Fischer  as  dioxy-dimethyl-purpuriue.  In  its  composi- 
tion it  is,  therefore,  a  dimethyl-xan thine, 

Carnine,  C-,H8N403,  was  isolated  in  1871  from  Ameri- 
can meat-extract  by  Weidel,  but  has  not  been  obtained 


CARNINE.  263 

from  iiiiiscle-tissue  itself.  It  has  also  been  obtained  from 
yeast  liquors  by  Sciiutzenberger,  and  from  urine  by 
PoucHET.  It  can  be  separated  from  the  meat  extract,  of 
which  it  forms  about  one  per  cent.,  by  the  following  method 
originally  employed  by  Weidel.  The  extract  is  dissolved 
in  six  or  seven  parts  of  warm  water,  then  concentrated 
baryta  "water  is  added,  avoiding  however  an  excess.  The 
filtrate  is  precipitated  by  basic  lead  acetate.  The  precipitate 
is  collected,  thoroughly  washed  and  pressed,  and  finally  it 
is  ref)eatedly  extracted  with  a  large  quantity  of  boiling 
water.  The  carnine  lead  salt  is  thus  dissolved  out,  the 
filtrate,  after  removal  of  the  lead  by  hydrogen  sulphide, 
is  evaporated  to  a  small  volume.  The  concentrated  solu- 
tion tiius  obtained  is  treated  with  silver  nitrate,  which 
gives  a  precipitate  of  silver  chloride  and  of  the  silver  salt 
of  carnine.  By  treatment  with  ammonium  hydrate  the 
silver  chloride  can  be  completely  removed  from  the  pre- 
cipitate, whereas  the  silver  compound  of  carnine  is  in- 
soluble in  that  reagent.  To  obtain  pure  carnine  the  silver 
salt  is  decomposed  with  hydrogen  sulphide,  and  the  filtrate 
after  purification  by  bone-black  is  evaporated  to  crystalli- 
zation. 

Carnine  forms  white  crystalline  masses,  which  on  drying 
become  loose  and  chalk-like.  It  is  very  difficultly  soluble 
in  cold  water,  easily  and  completely  in  boiling  water,  and 
recrystallizes  on  cooling.  It  is  insoluble  in  alcohol  and 
ether.  The  taste  is  decidedly  bitter,  and  the  reaction  is 
neutral.  The  base  is  not  precipitated  by  neutral  lead 
acetate,  but  is  precipitated  by  the  basic  salt  as  a  flocculeut 
white  precipitate,  soluble  in  boiling  water.  On  heating, 
carnine  decomposes  and  takes  fire,  and  at  the  same  time 
gives  off  a  peculiar  odor.  It  crystallizes  with  one  mole- 
cule of  water,  which  it  loses  at  100°-110°. 


264  LEUCOMAINES. 

The  hydrochloride,  C^HgN^Oa-HCl,  is  crystalline,  and 
decomposes  on  heating  with  concentrated  hydrochloric 
acid. 

The  platinochloride,  C-HgN^Og.HCl.PtCl^,  forms  a  fine 
sandy,  gold-yellow  powder. 

With  silver  nitrate,  carnine  unites  to  form  a  white  floccu- 
lent  precipitate,  insoluble  in  nitric  acid  or  in  ammonium  hy- 
drate.  Its  formula  corresponds  to  2(C7H^AgN^03)-|- AgNOg. 

Carnine  is  not  aifected  by  prolonged  boiling  with  con- 
centrated barium  hydrate.  Bromine  water  decomposes  it 
with  the  evolution  of  gas  and  the  formation  of  hypoxan- 
thine.  This  change  takes  place  according  to  the  following 
equation  : 

C,H,N,03+2Br=C,H,N,O.HBr+CH3Br+C02. 

A  similar  decomposition  into  hypoxanthine  is  brought 
about  by  the  action  of  nitric  acid,  though  in  this  case 
oxalic  acid  and  a  yellow  body  are  formed.  When  carnine 
is  evaporated  with  chlorine  water  containing  a  little  nitric 
acid,  the  residue,  on  contact  with  ammonia,  gives  a  rose-red 
color  (murexide  test).  This  is  due,  according  to  Weidel, 
to  the  formation  of  hypoxanthine,  but  it  has  since  been 
shown  that  the  latter  base  does  not  give  this  reaction,  and 
hence  it  is  due  to  the  production  of  xanthine,  or  some 
similar  body. 

The  physiological  action  of  carnine  has  been  examined 
somewhat  by  Brucke,  and  according  to  him  it  is  not  very 
poisonous.  The  only  effect  observed,  when  taken  inter- 
nally, was  a  fluctuation  in  the  rate  of  the  heart-beat,  though 
even  this  was  by  no  means  definite  in  its  nature. 

A  Base,  CJiJSi^O,  was  obtained  by  Gautier  from 
fresh  muscle  tissue  of  beef,  according  to  the  method  given 


SPERMINE.  265 

on  page  269,  and  on  aceonnt  of  a  reseinhlanee  in  some  of 
its  properties  with  xanthine,  he  named  it  pseudoxanthine. 
This  name  is  very  inappropriate,  not  only  because  it  differs 
so  much  in  its  empirical  formula  from  that  of  xanthine, 
CjH^N^Og,  but  also  because  the  term  pseudoxanthine  has 
already  been  applied  by  Schultzen  and  Filehne  to  a 
body  isomeric  M'ith  xanthine,  which  was  obtained  by  the 
action  of  sulphuric  acid  on  uric  acid. 

The  free  base  forms  a  light-yellow  powder,  slightly 
soluble  in  cold  water,  soluble  in  weak  alkali  and  in  hydro- 
chloric acid.  The  hydrochloride  is  very  soluble,  and  it 
forms  stellate  prisms  with  curved  faces,  which  resemble 
the  corresponding  salt  of  hypoxanthine,  and  to  some  extent, 
also,  the  whetstone-shaped  crystals  of  uric  acid. 

Like  xanthine,  its  aqueous  solution  is  precipitated  in  the 
cold  by  mercuric  chloride,  silver  nitrate,  and  by  ammo- 
niacal  lead  acetate,  but  not  by  normal  lead  acetate.  On 
evaporation  with  nitric  acid,  the  residue  gives,  on  contact 
with  potassium  hydrate,  as  in  the  case  of  xanthine,  a  beauti- 
ful orange-red  coloration  (xanthine  reaction).  It  differs 
from  xanthine,  not  only  in  its  empirical  composition,  but 
also  in  its  greater  solubility,  and  in  its  crystalline  form. 
It  is  possible  that  this  base,  on  account  of  its  great  resemb- 
lance to  xanthine,  may  have  been  mistaken,  at  different 
times,  for  that  compound. 

Spermine,  CjH^N,  is  the  basic  substance  obtained  by 
ScHREiNER  (1878)  from  semen,  calf's  heart,  calf's  liver, 
bull's  testicles,  and  also  from  the  surface  of  anatomical 
specimens  kept  under  alcohol.  Previous  to  this,  however, 
it  had  been  known  for  a  long  time  under  the  name  of 
"Charcot-Neumaxn  crystals,"  which  are  the  phosphate 
of  spermine.     These  peculiarly  shaped  crystals  have  been 

23 


266  LEUCOMAIlSrES. 

found  in  the  sputa  of  a  case  of  emphysema  with  catarrh, 
in  the  bronchial  discharges  in  acute  bronchitis,  as  well 
as  in  sputa  of  chronic  bronchitis,  in  the  blood,  spleen,  etc., 
of  leucocythsemias  and  ansemics,  and  in  the  normal  marrow 
of  human  bones,  as  well  as  in  human  semen.  Altogether 
it  seems  to  have  a  very  wide  distribution,  especially  in  cer- 
tain diseases,  as  in  leucocythpemia. 

It  can  be  prepared  from  fresh  human  semen  in  the  fol- 
lowing manner :  The  semen  is  Avashed  out  of  linen  by  a 
little  warm  water,  evaporated  to  dryness,  boiled  with  alco- 
hol, and  the  insoluble  portion  is  allowed  to  subside  by 
standing  some  hours.  The  precipitate  is  filtered  off,  washed, 
and  dried  at  100°.  This  residue,  containing  the  spermine 
phosphate,  is  triturated,  and  then  extracted  with  warm 
ammoniacal  water.  From  this  solution,  on  slow  evapora- 
tion, the  phosphate  crystallizes  in  its  peculiar-shaped 
crystals. 

The  free  base  is  obtained,  on  decomposing  the  phosphate 
with  baryta  and  evaporating  the  filtrate,  as  a  colorless 
liquid,  which,  on  cooling,  crystallizes.  From  alcohol  it 
crystallizes  in  wavellite-shaped  crystals,  which  readily 
absorb  water  and  carbonic  acid  from  the  atmosphere. 
They  are  readily  soluble  in  water  and  in  absolute  alcohol, 
almost  insoluble  in  ether,  and  possess  a  strongly  alkaline 
reaction.  When  heated  with  platinum  it  gives  off  thick, 
white  fumes,  and  a  weak  ammoniacal  odor.  The  aqueous 
solution  of  the  base  is  precipitated  by  phosphomolybdic 
and  phosphotungstic  acids,  tannic  acid,  gold  and  platinum 
chlorides. 

The  hydrochloride,  C2HgN.HCl,  crystallizes  in  six- 
sided  prisms,  united  in  tufts,  and  is  extremely  soluble  in 
water,  almost  insoluble  in  absolute  alcohol  and  ether. 

The    aurochloride,    C2H5N.HCI.AUCI3,    forms   shining. 


SPERMINE.  267 

golden-yellow,  irregular  plates,  aud  when  freshly  precipi- 
tated it  is  easily  soluble  in  water,  alcohol,  and  ether,  but 
the  dried  salt  is  incompletely  soluble  in  water.  The  aque- 
ous solution,  treated  with  magnesium,  gives  off  a  sperm- 
like  odor.     Tho  platinochloride  crystallizes  in  prisms. 

The  phosphate,  (C2H5N)2.H3PO,"+3H20  (?),  forms  prisms 
and  slender  double  pyramids.  It  is  difficultly  soluble  in 
hot  water,  insoluljle  in  alcohol,  easily  soluble  in  dilute 
acids,  alkalies,  and  alkali  carbonates.  It  melts  with 
decomposition  at  about  170°.  It  is  probable  that  the 
above  formula  does  not  represent  the  salt  as  found,  and 
from  theoretical  considerations  Ladexburg  is  inclined  to 
think  that  Schreiner's  phosphate  has  the  composition 
(C,H,XH),Ca(PO,\. 

Ladenburg  aud  Abel  have  recently  (March,  1888) 
prepared  a  compound,  ethyleneimine,  which  is  isomeric, 
possibly  identical  with  spermine.  The  reaction  whereby 
it  is  prepared  is  similar  to  the  one  by  which  Ladenburg 
effected  the  synthesis  of  piperidine.  Ethylenediamine  hy- 
drochloride is  su1)jected  to  dry  distillation,  when  it  decom- 
poses into  ammonium  chloride  and  the  hydrochloride  of 
the  new  base.     Thus  : 

CH^NH^.HCl      CH^ 

I  =  I      /NH.HCl+NH^Cl. 

CH^NIL.HCl     CH2 

The  nuclein  of  the  spawn  of  salmon  has  been  found  by 
Miescher  to  exist  in  a  salt-like  combination  with  a  basic 
substance,  to  which  he  applied  the  name  protamine.  Pic- 
ARD  has  found  it  in  the  same  source,  together  with  hypo- 
xanthine  and  guanine,  but  no  xanthine.  The  formula 
assigned  to  this  base  is  quite  complex,  and  cannot  be  con- 
sidered  as   definitely  settled.       Analysis    of  the   platiuo- 


268  LEUCOMAINES. 

chloride  gave:  Pt=24.64,  C1=26.45,N=15.03,  C=  22.80, 
H=4,15,  0=6.93.  The  hydrochloride  forms  an  amor- 
phous, hygroscopic,  sticky  mass. 

Leucomaines  of  the  Creatinine  Group. 

The  knowledge  of  the  formation  of  basic  substances 
(ptomaines)  in  the  presence  of  putrefaction  of  nitrogenous 
organic  matter,  led  to  a  series  of  investigations  having  for 
their  object  the  isolation  of  any  alkaloidal  bodies,  if  such 
existed,  from  the  normal  living  tissues  of  the  organism. 
A  number  of  compounds  possessing  alkaloidal  properties, 
such  as  the  xanthine  derivatives,  already  described,  had 
been  known  for  a  long  time,  although  their  physiological 
relation  to  the  animal  economy  was  little,  if  at  all,  under- 
stood. GuARESCHi  and  Mosso,  in  the  course  of  their 
researches  on  ptomaines,  were  among  the  first  to  direct 
their  attention  to  the  possible  presence  of  ptomaine-like 
bodies  in  fresh  tissues.  They  obtained  in  those  cases 
where  the  extraction  was  carried  on  without  the  use  of 
acids,  only  very  minute  traces  of  an  alkaloidal  body 
(possibly  choline),  and  an  inert  substance,  methyl-hydantoiu, 
which,  although  it  can  scarcely  be  classed  as  a  basic 
compound,  is  closely  related  to  creatine,  and  for  this  reason 
will  be  described  at  the  end  of  this  section.  Other  Italian 
chemists,  as  Paterno  and  Spica  and  Marino-Zuco,  had 
also  shown  that  the  normal  fluids  and  tissues  of  the  body 
were  capable  of  yielding  substances  alkaloidal  in  nature,  and 
these  were  regarded  by  them  as  identical  with,  or  similar 
to,  the  23tomaiues  of  Selmi. 

Liebreich,  in  1869,  discovered  in  normal  urine  an 
oxidation-product  of  choline,  probably  identical  with 
betaine  (page  196),  and  Pouchet,  in  1880,  announced  the 
presence  in  the  same  secretion  of  allantoin,  carnine  (page 


THE    CREATININE    GROUP.  269 

280),  and  an  alkaloidal  base,  which,  however,  was  not 
obtained  at  that  time  in  sufficient  quantity  to  permit  a 
determination  of  its  character.  Subsequently  he  succeeded 
in  isolating  this  base  as  well  as  another  closely  related 
body,  both  of  which  will  l^e  described  in  their  proper 
place.  Gautier  has  been  engaged  for  a  number  of  years 
in  the  study  of  the  leucomaines  occurring  in  fresh  muscle 
tissue,  and  he  has  succeeded  in  isolating  several  new 
compounds. 

A  number  of  these  substances  are  credited  with  possess- 
ing an  intensely  poisonous  action,  and  if  such  is  the  case 
it  is  very  evident  that  any  undue  accumulation  of  such 
bases  in  the  system,  resulting  from  an  interference  in  the 
elimination,  may  give  rise  to  serious  disturl)ances.  The 
amount  of  these  substances  present  in  the  daily  yield  of 
the  urine  is  very  small,  so  small,  indeed,  that  we  must 
rather  look  upon  this  small  quantity  as  having  escaped 
oxidation  in  the  body.  It  is  well  known  that  the  living 
tissues  possess  an  enormous  oxidizing  and  reducing  power, 
and,  according  to  Gautier,  there  is  constantly  going  on  in 
the  normal  tissues  of  the  body  a  cycle  of  changes — the 
formation  of  leucomaines  and  their  subsequent  destruction 
by  oxidation,  before  they  have  accumulated  in  sufficient 
quantity  to  produce  poisonous  effects. 

The  following  method  was  employed  by  Gautier  in 
his  study  of  the  leucomaines  of  muscle  tissue :  The 
finely  divided  fresh  beef-meat  or  the  Liebig's  meat  extract 
is  treated  with  twice  its  weight  of  water,  containing  0.25 
gram  of  oxalic  acid,  and  one  to  two  c.  c.  of  commercial 
peroxide  of  hydrogen  per  litre.  The  purpose  of  these 
precautions  is  to  prevent  fermentation.  At  the  end  of 
twenty-four  hours  the  liquid  is  raised  to  the  boiling-point, 
then  filtered  through  linen,  and  the  residue  is  thoroughly 

23* 


270  LEUCOMAINES. 

squeezed.  The  filtrate  is  again  raised  to  the  boiling-point 
in  order  to  coagulate  any  remaining  albumen,  and  finally 
filtered  through  paper.  The  clear  liquid  thus  obtained  is 
evaporated  in  a  vacuum  at  a  temperature  not  exceeding 
50°,  and  the  acid  syrupy  residue  is  extracted  with  99 
per  cent,  alcohol ;  the  alcoholic  extract  is  in  turn 
evaporated  in  a  vacuum,  and  the  residue  taken  up  with 
warm  alcohol  of  the  same  strength.  The  filtered  alcoholic 
solution  is  set  aside  fi^r  twenty-fi^ur  hours,  and  any  deposit 
which  fiarms  is  removed  by  filtration  ;  ether  (65°)  is  then 
added  as  long  as  a  precipitate  continues  to  form,  and  the 
whole  is  again  allowed  to  stand  for  twenty-four  hours. 
The  ether- alcoholic  filtrate  from  this  precipitate  is  evapo- 
rated first  on  the  water  bath,  and  finally  in  a  vacuum; 
the  slight  residue  obtained  contains  a  small  quantity  of 
basic  substances  possessing  an  odor  of  hawthorn. 

The  syrupy  precipitate  produced  by  the  ether  partially 
crystallizes  on  standing;  a  little  absolute  ether  is  then 
added,  and  after  standing  several  days  more  the  liquid  is 
separated  by  means  of  an  aspirator  from  the  deposit  of 
crystals  (A).  These  are  first  washed  with  99  per  cent, 
alcohol,  and  then  extracted  with  boiling  95  per  cent, 
alcohol.  The  alcoholic  solution,  concentrated  by  evapor- 
ation, gives,  on  cooling,  a  deposit  of  lemon-yellow  colored 
crystals  of  xantho-creatiuine  (B),  from  the  mother-liquor 
of  which  there  separates  a  crop  of  new  crystals  (C).  The 
residue  of  the  crystals  (A)  left  after  treatment  with  the 
boiling  95  per  cent,  alcohol  is  extracted  with  boiling  water, 
which  afterward  gives  a  slight  deposit  of  yellowish-white 
crystals  of  amphi-creatiue  (D).  The  aqueous  mother-liquors 
on  concentration  yield  another  deposit  of  orange  colored 
crystals  of  cruso-creatinine  (E).  Gautier  has,  further- 
more, separated  three  other  bases  from  the  mother-liquors 


CRUSO-CREATININE.  271 

of  the  crystals  obtained  as  above.  Thus,  a  base  which  he 
named  pseudoxanthine  is  stated  to  have  been  obtained  by 
evaporating  the  alcoholic  mothcr-liqiiors  of  B,  D,  E  (?)  in 
a  vacuum,  taking  up  the  residue  with  water,  and  precipi- 
tating the  hot  solution  with  copper  acetate.  The  precipitate 
is  decomposed  with  hydrogen  sulphide,  and  the  aqueous 
solution,  filtered  whilst  boiling  hot,  yields  a  deposit  of  a 
sulphur-yellow  powder  of  pseudoxanthine.  Thus,  by  the 
use  of  alcohol,  ether,  and  water,  Gautier,  according  to  his 
statement,  has  succeeded  in  obtaining  a  sharp  separation 
between  these  bases.  The  importance  of  the  subject  is  such 
as  to  require  not  only  confirmation  of  the  results  arrived  at 
by  Gautier,  but  also  a  more  detailed  and  exact  study  of 
the  chemical  and  physiological  behavior  of  these  bodies. 

To  the  physiological  chemist  these  substances  are  of 
especial  interest  because  of  the  possible  relation  which  they 
bear  to  the  formation  of  creatine  and  creatinine  in  the 
muscle.  It  will  be  seen  that  in  the  leucomaines  of  this 
group,  as  well  as  in  those  of  the  uric  acid  group,  hydro- 
cyanic acid  plays  a  very  important  part  in  the  molecular 
structure  of  these  bases.  Just  what  the  function  of  this 
cyanogen  group  is  so  far  as  the  vital  activity  of  the  tissues 
is  concerned  we  know  very  little,  though  recent  investiga- 
tions seem  to  show  that  the  seat  of  the  cyanogen  formation 
lies  within  the  nucleated  cell,  and  is  intimately  connected 
with  the  functions  of  the  uuclein  molecule. 

Cruso-creatinine,  CjHgN/),  forms  orange-yellow  crys- 
tals which  are  slightly  alkaline  in  reaction,  and  possess  a 
somewhat  bitter  taste.  It  yields  a  soluble,  non-deliquescent 
hydrochloride  crystallizing  in  bundles  of  needles  ;  also  a 
soluble  platinochloride  which  forms  tufts  of  beautiful, 
slender  prisms.     The  auroehloride  is  obtained  as  slightly 


272  LEUCOMAINES. 

soluble,  crystalline  grains,  and,  like  the  platinum  double 
salt,  is  partially  decomposed  on  heating.  It  is  not  precipi- 
tated by  acetate  of  zinc  or  by  mercuric  nitrate,  but  is  pre- 
cipitated in  the  cold  by  solutions  of  alum.  Zinc  chloride 
produces  in  somewhat  concentrated  solutions  a  pulverulent 
precipitate  which  dissolves  on  heating,  and  recrystallizes 
affain  when  it  cools.  Like  xantho-creatinine  it  is  not  thrown 
out  of  solution  by  oxalic  or  nitric  acid,  and  is  thus  distin- 
guished from  urea  and  guanidine  ;  nor  is  it  precipitated  by 
acetate  of  copper — a  distinction  from  xanthine  derivatives. 
Mercuric  chloride  produces  an  abundant  flocculent  precipi- 
tate which  on  heating  partially  dissolves,  decomposing  at 
the  same  time.  Sodium  phosphomolybdate  gives  a  heavy 
yellow  precipitate,  whereas  potassium  mercuro-chloride  and 
iodine  in  potassium  iodide  have  no  effect.  Potassium  ferri- 
cyanide  is  not  reduced.  This  base  differs  in  its  composition 
from  creatinine  by  HON,  the  elements  of  hydrocyanic  acid, 
but  in  its  crystalline  form  and  alkaline  reaction,  and  some 
other  properties,  it  would  seem  to  be  closely  related  to  this 
latter  substance.  Because  of  this  apparent  relationship  and 
its  golden-yellow  color,  Gautier  named  it  cruso-creatinine. 

Xantho-creatinine,  CsHmN^O,  is  the  most  abundant 
of  muscle  leucomaines.  It  crystallizes  in  sulphur-yellow, 
thin  spangles,  consisting  of  nearly  rectangular  plates  which 
resemble  somewhat  those  of  cholesterin.  It  is  soft  and 
talc-like  to  the  touch  ;  possesses  a  slightly  bitter  taste,  and 
when  dissolved  in  boiling  alcohol  it  gives  off"  the  odor  of 
acetamide,  though  ordinarily  in  the  cold  it  has  a  slight 
cadaveric  odor.  When  heated,  the  substance  evolves  an 
odor  of  roast  meat,  carbonizes  in  part,  and  yields  ammonia 
and  methylamine.    The  crystals  are  amphoteric  in  reaction. 


XANTHO-CREATININE.  273 

are  soluble  iu  cold  water,  and  cau  be  recrystallized  from 
boiliug  99  per  cent,  alcohol. 

It  forms  a  hydrochloride  crystallizint*- in  plumose  needles, 
and  a  very  soluble  platinochloride;  the  aurochloride  crys- 
tallizes with  difficulty.  Like  (creatinine,  it  is  precipitated 
by  zinc  chloride ;  the  yellowish-white  precipitate  dissolves 
with  partial  dissociation  on  warming,  and  on  cooling  sepa- 
rates as  isolated  or  stellate  groups  of  fine  needles  which 
possess  the  composition  (C5HiyN^O)2ZnCl2  Silver  nitrate 
throws  down,  in  the  cold,  a  flocculent  precipitate  which 
likewise  dissolves  on  heating,  and  recrystallizes  in  needles. 
Mercuric  chloride  produces  a  yellowish-white  precipitate. 
It  is  not  precipitated  by  oxalic  or  nitric  acid,  nor  by  potas- 
tassio-mercuric  chloride,  or  iodine  in  potassium  iodide. 
Tannin  produces  in  time  a  slight  turbidity,  whilst  sodium 
phosphomolybdate  gives  a  heavy  yellowish  precipitate. 
This  base  is  distinguished  from  the  members  of  the  uric 
acid  group  by  not  giving  a  precipitate  with  copper  acetate, 
not  even  on  heating. 

On  gentle  oxidation  with  potassium  permanganate  it  is 
converted  into  a  black  substance  insoluble  in  acids  and 
alkalies,  and  resembling  azulmic  acid.  By  treatment  with 
recently  precipitated  mercuric  oxide,  it  yields  a  substance 
which  can  be  recrystallized  from  boiling  93  per  cent, 
alcohol  in  needles  which  possess  a  slight  alkaline  reaction, 
and  forms  a  slightly  soluble,  crystalline  platinochloride. 
This  new  substance  is  precipitated  from  alcoholic  solution 
by  the  addition  of  ether,  as  a  mass  of  beautiful,  white,  silky 
needles  resembling  caffeine.  These  crystals  melt  at  174°; 
caffeine  melts  at  17<S°. 

Xantho-creatine,  given  iu  fairly  large  doses,  is  poison- 
ous, producing  in  animals  depression,  somnolence,  and 
extreme  fatigue,  accompanied  by  frequent  defecation  and 


274  LEUCOMAINES. 

v^omiting.  In  its  general  properties  this  base  resembles 
creatinine  very  much,  and  it  was  on  account  of  this  resem- 
blance and  its  yellow  color  that  it  was  named  xantho-crea- 
tinine.  This  relation  becomes  especially  evident  since  this 
base  appears  in  the  physiologically  active  muscle  at  the 
same  time  with  creatinine,  constituting  sometimes  one-tenth 
of  the  creatinine  present.  Monari  has  found  this  base  in 
the  aqueous  extract  of  the  muscles  of  an  exhausted  dog, 
and  also  in  the  urine  of  soldiers  tired  by  several  hours' 
walk.  He  also  demonstrated  its  presence  in  the  urine  of  a 
clog  after  previous  injection  of  creatinine. 

Amphi-creatine,  CgHjgN^O^,  is  slightly  soluble  and 
crystallizes  from  boiling  water  in  yellowish-white  oblique 
prisms,  which  possess,  if  any,  a  slightly  bitter  taste. 
When  heated  to  100°  it  decrepitates  somewhat,  and  at 
110°  it  becomes  opaque  white.  Potassium  hydrate  does 
not  decompose  it  in  the  cold.  Although  a  weak  base,  it 
combines  to  form  salts  just  as  the  preceding  members  of 
this  group.  The  hydrochloride  is  crystalline,  and  is  not 
deliquescent ;  the  platinochloride  forms  rhombic  plates, 
which  are  soluble  in  water,  but  are  insoluble  in  absolute 
alcohol ;  the  aurochloride  crystallizes  in  easily  soluble,  very 
small,  microscopic  crystals,  which  are  tetrahedral  to  hexa- 
hedral  in  their  habit.  It  is  not  precipitated  by  copper 
acetate  or  by  mercuric  chloride ;  nor  does  it  give  the 
murexide  test,  or  the  xanthine  reaction.  Sodium  phospho- 
molybdate  produces  a  yellow,  pulverulent  precipitate.  In 
its  properties  it  resembles  creatine,  and  indeed  Gautier 
thinks  it  may  be  possibly  a  combination  of  creatine, 
C4H9N3O2,  and  a  base  CgHj^N^Og,  which,  it  will  be  seen, 
differs  from  the  former  only  by  a  HON  group.  This 
second  compound,  if  it  really  exists,   has  an   analogy  in 


A    BASE,    CiiH^^Ni^Oj.  275 

oruso-creatiuine,  the  relation  of  whieh  to  ereiitiaiue  may  be 
expressed  by  the  equation  : 

CgH^N^O  =  C.H.NgO  +  HCN. 

CbUSO-CUEATININE.  CUEATININE. 

In  a  similar  manner,  amj)hi-creatine  may  be  regarded  as 

Ampih-creatimne.  Creatinine. 

A  Base,  CnHg^NjyOj,  was  isolated  by  Gautier  from 
the  mother-liquors  of  xantho-creatiniue.  It  crystallizes  in 
colorless  or  yellowish,  thin,  apparently  rectangular  plates, 
which  are  tasteless,  and  possess  an  amphoteric  reaction. 
The  hydrochloride  forms  bundles  of  fine  needles;  the  sul- 
phate yields  a  confused  mass  of  needles  ;  the  platinochlo- 
ride  is  soluble,  non-deliquescent,  and  crystalline.  When 
heated  with  water  in  a  sealed  tube  at  180°-200°,  it  gives 
off  ammonia  and  carbonic  acid,  and  is  converted  into  a 
new  base,  which,  however,  has  not  been  studied.  This 
reaction  may  be  expressed  by  the  equation  : 

CuH,,N,,0,  =  2C,H^„N,0,-fCO(NH,)3 

Urea. 

The  urea  which  at  first  forms,  is,  in  turn,  decomposed, 
thus  : 

C0(NH,).  +  H20  =C02+2NH3. 

It  is  to  be  observed  that  this  base  differs  in  composition 
from  the  following  one  by  HCN,  the  hydrocyanic  acid 
molecule. 

A  Base,  Ci2H25Njj05,  was  obtained  from  the  mother- 
liquors  of  cruso-creatinine,  and  forms  rectangular  silky 
plates,  resembling  those  of  the  preceding  base  and  of 
xantho-creatinine.     It  forms  crystallizable  salts. 

These  complex  bases  will  require  further  study  in  order 


276  LEUCOMAINES. 

to  elucidate  their  physiology,  and  the  possible  connection 
which  they  may  have  with  the  formation  of  urea,  and  of 
the  creatinine  derivatives  already  described. 

/N(CH,).CH2 

MeTHYL-HYDANTOIX,   C4H6N2O2  =  CO^^TT  _  QQ  • 

— This  substance  was  obtained  by  Guareschi  and  Mosso 
(1883),  by  extracting  fresh  meat  with  1-1.5  volumes  of 
water  (without  addition  of  acid),  for  two  hours  at  50°-60°. 
The  aqueous  extract  was  evaporated  on  the  water  bath  and 
the  residue  was  extracted  with  95  per  cent,  alcohol.  This 
alcoholic  solution,  after  the  alcohol  was  driven  oif,  was 
taken  up  in  water,  filtered,  and  the  aqueous  solution  was 
first  extracted  with  ether,  then  rendered  alkaline  with 
ammonia,  and  again  extracted  with  ether.  The  alkaline 
ether  extract  gave  on  evaporation  a  white  crystalline  residue 
of  methyl-hydantoin.  The  amount  of  this  substance 
present  in  flesh  appears  to  be  quite  variable,  since,  at  times, 
none  whatever  can  be  extracted.  Albertoxi  has  isolated 
it  from  dog's  flesh.  Previous  to  its  discovery  in  flesh  by 
Guareschi  and  Mosso,  it  was  known  for  a  long  time  as  a 
decomposition-product  of  various  nitrogenous  bases  of  the 
body.  Thus,  Neubauer  prepared  it  by  heating  creati- 
nine with  barium  hydrate,  whilst  Huppert  obtained  it  by 
fusing  together  sarcosine  with  urea.  As  it  occurs  in  muscle 
it  is  probably  derived  from  the  creatine,  though  under 
what  conditions  this  splitting  up  takes  place  is  not  definitely 
known.  Acetic  and  lactic  acids  are  incapable  of  effecting 
this  change.  At  all  events,  it  belongs  to  the  ureides,  and 
is  intermediate  between  creatinine,  sarcosine,  and  urea. 

Methyl-hydantoin  forms  prisms  which  are  easily  soluble 
in  water  and  alcohol,  and  but  slightly  soluble  in  cold  ether. 


LEUCOMAINES    OF    EXPIRED    AIR.  277 

It  melts  at  156°  (Salkowski)  ;  at  159°-160°  (Guareschi 
and  Mosso).  Its  aqueous  solutiou  is  slightly  acid  iu  reac- 
tion. On  strong  heating  it  volatilizes.  When  fused  with 
potassium  hydrate  it  gives  off  ammonia;  it  reduces  mercuric 
nitrate  iu  the  cold.  Treated  with  mercuric  oxide  it  assumes 
an  alkaline  reaction,  and  the  filtrate  on  heating  yields 
metallic  mercury.  With  silver  oxide  it  forms  pearly  lan- 
ceolate plates  having  the  composition  C^HjNgOj.Ag.  It 
does  not  give  any  alkaloidal  reactions. 

Undetermined  Leucomaines. 

Leucomames  of  Expired  Air. 

It  was  shown  at  quite  an  early  period  that  exhalations 
from  animals  contain,  besides  an  increased  amount  of  car- 
bonic acid,  some  organic  matter,  the  nature  of  which,  on 
account  of  the  exceedingly  minute  quantity  iu  which  it 
occurs,  has  never  been  satisfactorily  determined.  Never- 
theless, various  observers  did  not  hesitate  to  ascribe  to  it 
the  ill  effects  consequent  upon  breathing  impure  air,  whilst 
at  the  same  time  the  carbonic  acid  formed  during  respira- 
tion was  considered  either  as  entirely  inert,  or  as  insignifi- 
cant in  its  action.  Thus,  res})ired  air  from  which  moisture 
and  carbonic  acid  have  been  removed,  but  which  still  contains 
the  organic  vapors,  has  been  found  to  be  highly  poisonous. 
On  the  other  hand,  if  the  respired  air  is  drawn  through  a 
red-hot  tube  to  destroy  the  organic  matter,  the  air  thus 
purified  is  capable  of  sustaining  life  even  in  presence  of  a 
large  percentage  of  carbonic  acid.  Whilst  it  cannot  be, 
therefore,  doubted  that  the  organic  matter  of  expired  air 
plays  a  most  important  part  in  producing  the  well-known 
noxious  effects  resulting  from  breathing  confined  and  vitiated 
air,  nevertheless  it  would  seem  from  experiments  made  by 

24 


278  LEUCOMAINES. 

Angus  Smith  that  the  increase  of  even  such  small  quanti- 
ties of  carbonic  acid  in  the  air,  as  from  0.04,  the  normal 
amount  present,  to  0.1  per  cent.,  is  capable  of  producing 
systemic  disturbances  characterized  by  a  decrease  in  the 
pulse-rate  and  an  increase  in  the  rate  of  respiration. 

Smith  is  consequently  of  the  opinion  that  the  constant 
lowering  of  the  pulse  in  impure  air  occasioned  by  the  pres- 
ence of  carbonic  acid,  must  have  a  depressing  effect  on 
the  vitality.  Whatever  ill  effects  the  carbonic  acid  may 
produce  of  itself,  it  remains  certain  that  this  gas  is  not  the 
most  potent  and  most  injurious  constituent  of  respired  air; 
and  the  investigations  of  Hammond,  Nowak,  Seegen, 
and  others,  point  conclusively  to  the  organic  matter  as  the 
direct  and  immediate  agent  which  produces  those  symp- 
toms of  sickness  and  nausea  experienced  in  badly  ventilated 
closed  rooms. 

Of  special  importance  to  the  sanitarian  and  physician  is 
the  recent  work  on  the  nature  and  action  of  the  poisonous 
principle  of  expired  air,  which  has  been  made  by  Brown- 
Sequaed,  d'Aesonval,  and  K.  Wurtz.  The  first  two 
observers  found  that  the  vapors  exhaled  by  dogs,  when 
condensed,  and  the  aqueous  liquid  (20-44  c.  c.)  thus 
obtained  was  injected  into  other  animals  death  was  pro- 
duced, mostly  within  twenty-four  hours.  The  symptoms 
observed  were  dilatation  of  the  pupil,  increase  of  heart-beat 
to  240-280  per  minute,  which  may  last  for  several  days 
or  even  weeks,  whilst  the  temperature  remains  normal ; 
the  respiratory  movements  are  generally  slowed,  and  usu- 
ally there  is  observed  considerable  paralysis  of  the  pos- 
terior members.  Choleraic  diarrhoea  is  invariably  present. 
As  a  rule,  it  appears  that  larger  doses  cause  labored 
respiration,  violent  retching,  and  contraction  of  the  pupil. 
A  rapid  lowering  of  temperature,  0.5°  to  5°,  is  sometimes 


LEUCOMAINES    OF     EXPIRED    AIR.  279 

observed.  These  same  symptoms,  apparently  in  aggravated 
form,  were  obtained  when  the  liquid  had  been  previously 
boiled  for  the  purpose  of  destroying  any  germs  that  might 
be  present.  The  appearances  presented  on  post-mortem 
were  much  like  those  observable  in  cardiac  syncope.  From 
their  results  it  is  evident  that  expired  air  contains  an  ex- 
tremely violent  poison,  and  Brown-Sequard  is  of  the 
opinion  that  in  confined  air  the  continuous,  though  slowly 
exercised  influence  of  this  volatile  poison  produces  pul- 
monary phthisis. 

The  above  work  has  already  been  confirmed,  in  part,  by 
R.  WuRTZ,  who,  by  passing  expired  air  through  a  solution 
of  oxalic  acid,  has  obtained  besides  ammonia  a  volatile 
organic  base  which  is  precipitated  by  Bouchardat's 
reagent  and  by  potassio- mercuric  iodide.  It  is  said  to 
form  a  platinum  double  salt  crystallizing  in  short  needles, 
and  a  soluble  gold  salt.  When  heated  to  100°  it  gives  off 
a  peculiar  odor.  This  basic  substance  may  properly  be 
looked  upon  as  a  leucomaine. 

Sewer-air,  according  to  observations  made  by  Odling, 
contains  a  basic  substance  which  is  probably  in  composition 
a  compound  ammonia.  It  contains,  however,  more  carbon 
than  methylamine  and  less  than  ethylamine. 

It  should  be  remarked  that  Jackson  has  recently  (Dec. 
1887)  announced  the  presence  in  exj)ired  air  of  quantities 
of  carbon  monoxide  gas  sufficient  to  produce  the  ill  effects 
ordinarily  attributed  to  the  organic  matter.  The  presence 
of  this  poisonous  gas  must  first  be  fully  demonstrated  before 
it  can  be  takep  into  account  in  the  consideration  of  the 
toxicity  of  air ;  certainly,  even  if  present,  it  cannot  explain 
the  results  obtained  by  the  French  investigators  as  stated 
above. 


280  LEUCOMAINES. 

Leucomaines  of  the  Urine 

A  number  of  basic  substances  have  been  isolated  at 
diiferent  times  from  the  urine,  and  on  that  account  they 
may  be  properly  classed  as  leucomaines.  Thus,  Liebreich 
(1869)  found  in  the  urine  a  base  which  apparently  was  an 
oxidation-product  of  choline,  and  which  has  since  been 
regarded  as  identical  with  betaine.  Most  of  the  members 
of  the  uric  acid  group  of  leucomaines  have  been  detected 
in  the  urine  and  on  account  of  their  well-defined  nature 
they  are  described  by  themselves. 

In  1879,  Thudichum  announced  the  presence  in  the 
urine  of  four  new  alkaloids,  one  of  which  was  subsequently 
rediscovered  by  Salomon  and  named  paraxanthine  (page 
258).  Another  base  which  was  obtained  and  termed  reduciue, 
yielded  a  barium  salt  which  readily  reduced  the  salts  of 
silver  and  mercury.  Its  formula  probably  corresponds  to 
C12H24N6O9  or  CgHj^NgO^.  A  third  alkaloid  formed  a  zinc 
compound  having  the  composition  CgHgNgO.ZnO.  A  fourth 
base  is  said  to  give  a  compound  with  platinum  chloride, 
and  to  contain  an  aromatic  nucleus. 

In  1880,  PoucHET  announced  the  presence  of  carnine, 
CyHgN^Og,  and  of  another  base  which  he  subsequently  ana- 
lyzed and  found  to  have  either  the  composition  C^HjgN^Og 
or  C^Hj^N^Og.  This  substance  formed  deliquescent  fusi- 
form crystals,  sometimes  crystallized  in  bundles  or  irregular 
spheres,  which  possessed  a  slightly  alkaline  reaction  and 
combined  with  acids  to  form  crystallizable  salts.  It  was 
soluble  in  dilute  alcohol,  almost  insoluble  in  strong  alcohol, 
insoluble  in  ether.  The  hydrochloride  yielded  double  salts 
with  gold  chloride,  platinum  chloride,  and  mercuric  chloride. 
The  platiuochloride  formed  deliquescent  golden-yellow 
rhombic  prisms.     This  base  occurred  in  the  dialysate  (see 


LEUCOMAINES    OF    THE    UKINE.  281 

page  211).  From  the  non-dialyzable  portion,  Pouchet 
obtained  another  base  corresponding  to  the  formula  C3H5NO2. 
It  yields  precipitates  with  the  general  alkaloidal  reagents,  is 
altered  on  exposure  to  air,  and  is  resinified  bv  hydrochloric 
acid.  On  the  addition  of  platinum  chloride  it  is  rapidly 
oxidized,  but  does  not  yield  a  platinochloride.  The  same 
author  regards  the  urine  as  containing  very  small  quantities 
of  some  pyridine  bases  which  are  analogous  or  identical  with 
those  obtained  by  Gautier  and  Etard  from  decora- 
posing  fish. 

The  distinguished  Italian  toxicologist  Selmi  was  perhaps 
the  first  to  draw  attention  to  the  probable  formation  of 
basic  substances  in  the  living  body  during  those  patho- 
logical changes  brought  on  by  the  presence  of  pathogenic 
germs;  and  in  a  memoir  presented  to  the  Academy  of 
Sciences  of  Bologna,  in  December,  1880,  he  announced 
that  infectious  diseases,  or  those  in  which  there  occurs  an 
internal  disarrangement  of  some  element,  either  plasmic  or 
histological,  must  be  accompanied  or  followed  by  an  elim- 
ination of  more  or  less  characteristic  products,  which  would 
be  a  sign  of  the  pathological  condition  of  the  patient.  To 
support  this  theory,  he  examined  a  number  of  pathological 
urines  and  succeeded  in  obtaining  from  them  basic  sub- 
stances some  of  which  were  poisonous,  others  not.  Thus, 
a  specimen  of  urine  from  a  patient  with  progressive 
paralysis  gave  two  bases  strongly  resembling  nicotine  and 
coniiue;  from  other  pathological  urines  the  bases  obtained 
usually  had  either  an  ammoniacal  or  trimethylamiue  odor. 
An  apparent  strong  confirmation  of  Selmi's  theory  is  seen 
in  the  observations  made  by  Bouchard,  Yilliers, 
Lepine,  Gautier,  and  others,  all  of  whom  have  found 
basic  substances  in  the  urine  of  various  diseases.  Unfortu- 
nately none  of  these  bases  supposedly  characteristic  of  patho- 

24* 


282  LEUCOMAINES. 

logical  urines  have  been  isolated  in  a  chemically  pure  con- 
dition ;  nor  has  the  study  of  normal  urine  been  carried 
sufficiently  far  to  show  the  positive  absence  of  such  bodies. 

LeuGomaines  of  the  Saliva. 

According  to  the  statement  of  Gautier  (1881),  normal 
human  saliva  contains  divers  toxic  substances  in  small 
quantities  which  differ  very  much  in  their  action  according 
to  the  time  of  their  secretion,  and  probably  according  to 
the  individual  gland  in  which  they  are  secreted.  The 
aqueous  extract  of  saliva  at  100°  is  poisonous  or  narcotic 
in  its  action  toward  birds.  To  show  the  presence  of  basic 
substances,  the  aqueous  extract  was  slightly  acidulated  with 
dilute  hydrochloric  acid,  then  precipitated  by  Mayer's 
reagent;  the  precipitate  was  washed,  then  decomposed  by 
hydrogen  sulphide,  and  the  solution  filtered.  The  filtrate 
on  evaporation  gave  a  residue  consisting  of  microscopic 
slender  needles  of  a  soluble  hydrochloride.  This  salt, 
purified  by  extraction  with  absolute  alcohol,  forms  soluble 
crystalline,  but  easily  decomposable  double  salts  with 
platinum  chloride  and  with  gold  chloride.  The  solution 
of  the  hydrochloride  produces  an  immediate  precipitate  of 
Prussian  blue  in  a  mixture  of  potassium  ferricyanide  and 
ferric  chloride,  and  when  injected  into  birds  produces  a 
condition  of  stupor. 

Leucomaines  from  other  Tissues  of  the  Body. 

Selmi's  work  upon  the  formation  of  ptomaines  during 
the  process  of  putrefaction  led  many  investigators  to  doubt 
the  exact  origin  of  these  bases  as  due  to  the  decomposition 
of  the  proteid  or  other  complex  molecules.  To  substan- 
tiate this,  a  number  of  chemists,  especially  Italian,  endeav- 


LEUCOMAINES  FROM   TISSUES  OF   THE  BODY.      283 

ored  to  show  that  Selmi's  bases,  to  a  large  extent  at 
least,  exist  preformed  in  the  various  tissues.  Paterno 
aud  Spica  (1882),  succeeded  in  extractinp;  from  fresh  blood 
as  well  as  from  fresh  albumen  of  eggs  substances  identical, 
or  at  least  similar,  to  those  designated  under  the  name  of 
ptomaines.  Their  observations,  however,  were  confined  to 
the  detection  of  alkaloidal  reactions  in  the  various  extracts 
obtained  by  Dragendorff's  method,  and  at  no  time  were 
they  in  possession  of  a  definite  chemical  individual. 
Marino- Zuco  (1885)  was  more  successful,  inasmuch  as 
he  succeeded  in  obtaining  from  fresh  tissues  and  organs 
relevant  quantities  of  a  base  identical  with  choline,  and,  in 
addition,  he  obtained  extremely  minute  traces  of  other 
alkaloidal  bodies.  One  of  these,  obtained  by  the  Stas 
method  from  the  liver  and  spleen  of  an  ox,  exhibited  in 
hydrochloric  acid  solution  a  beautiful  violet  fluorescence 
resembling  very  much  that  of  the  salts  of  quinine.  A 
similar  base,  probably  identical  with  this  one,  was  obtained 
by  Bence  Jones  and  Dupre  (1866)  from  liver,  nerves, 
tissues,  and  other  organs,  aud  was  named  by  them  "  animal 
chinoidine."  A  greenish-blue  fluorescence  is  frequently 
observable  in  the  alcoholic  extracts  of  decomposing  glue 
as  well  as  from  other  putrefying  substances.  From  a 
number  of  very  thorough  experiments,  he  concluded  that 
basic  substances  do  not  preexist  in  fresh  organs,  but  that 
the  acids  employed  in  the  process  of  extraction  exert  a 
decompo.sing  action  upon  the  lecithin  present  in  the  tissues, 
resulting  in  the  formation  of  choline.  He  further  showed 
that  the  method  of  Drac4ENDOrff,  on  account  of  the 
larger  quantity  of  extractives  which  form,  invariably  gave 
a  larger  yield  of  this  base  than  did  the  Stas-Otto  method. 
Similar  observations  were  made  by  Guareschi  and  Mosso, 
by  Coppola  and  others.     At  the  present  time  there  is  no 


284  LEUCOMAINES. 

doubt  that  some  basic  substances,  among  these  choline,  can 
be  formed  by  the  action  of  reagents,  and,  on  the  other 
hand,  it  is  equally  well  demonstrated  that  similar  bases  do 
preexist  in  the  physiological  condition  of  the  tissues  and 
fluids  of  the  body. 

Recently  R.  Wurtz  has  obtained  from  normal  blood  a 
number  of  crystalline  products  of  alkaline  reaction,  which 
form  well-crystallizable  double  salts  with  gold,  platinum, 
and  mercuric  chlorides.  These,  however,  have  not  been 
as  yet  subjected  to  analysis,  because  of  the  minute  quan- 
tities which  were  isolated. 

A  substance  of  uncertain  character  has  been  isolated  by 
Capitan  and  Charrin  from  blue  pus,  and  named  pyo- 
cyanine.  Dilute  sulphuric  acid  withdraws  it  from  the 
chloroformic  solution  and  at  the  same  time  becomes  red. 
It  is  said  to  reduce  ferric  salts,  but  beyond  this  nothing 
definite  is  known  as  to  the  nature  or  origin  of  this  substance. 

MoRELLE  (1886)  showed  the  presence  in  the  spleen 
of  the  ox  of  a  base,  the  hydrochloride  of  which  crystallized 
in  deliquescent  needles  and  likewise  formed  crystalline 
platino-  and  aurochlorides.  From  experiments  made  by 
Laborde,  the  base  would  seem  to  possess  decided  toxic 
properties,  bringing  on  a  dyspuoeic  condition  with  con- 
vulsive movements  and  loss  of  motion.  The  post-mortem 
examinations  revealed  an  extended  visceral  oedematous 
infiltration,  and  stoppage  of  the  heart  in  systole. 

A.  W.  Blyth  has  claimed  to  have  isolated  from  milk 
two  alkaloidal  substances,  namely  galactine,  the  lead  salt 
of  which  is  said  to  have  the  formula  Pb^OgCg^HigN^Ogj, 
and  lactochrome,  the  mercury  salt  of  which  is  represented 
by  the  formula  HgOCgHigNOg. 


VENOMS    OF    POISONOUS    SERPENTS.  285 

Leucomaines  of  the  Venoms  of  Poisonous  Serpents 

The  study  of  the  chemistry  of  tlie  venoms  of  serpents 
and  of  batrachians  is  frauglit  with  so  many  difficulties  and 
with  so  much  danger,  that  we  cannot  wonder  at  the  present 
unsatisfactory  condition  of  our  knowledge  in  regard  to  the 
poisonous  principles  which  they  contain.  Much  of  the  work 
that  has  been  done  hitherto  is  not  only  inaccurate  and  very 
contradictory,  but  is  far  from  meeting  the  requirements  of 
exact  toxicologiciil  research.  From  recent  investigations 
it  seems,  however,  to  be  quite  certain  that  the  most  active 
constituent  of  the  venoms  of  serpents  is  not  alkaloidal  in 
its  nature  as  has  been  supposed  by  some.  In  1881 
Gautier  announced  the  isolation  of  two  alkaloids  from 
the  venom  of  the  cobra  which  gave  precipitates  with  tannin, 
Mayer's  reagent,  Nessler's  reagent,  iodine  in  potas- 
sium iodide,  etc.  They  formed  crvstallizable  platinochlo- 
rides  and  aurochlorides,  and  also  crystalline,  neutral,  some- 
what deliquescent  hydrochlorides.  The  neutral  or  slightly 
acid  solutions  produced  an  immediate  precipitate  of  Prus- 
sian blue  in  a  mixture  of  jiotassium  ferricyanide  and  ferric 
chloride.  These  substances  possess  a  decided  physiological 
action,  though  Gautier  himself  does  not  consider  them 
to  be  the  most  dangerous  constituents  of  the  venoms.  This 
observation  of  Gautier  as  to  the  presence  of  distinct  basic 
substances  in  venoms  is  at  variance  with  that  of  Wolcott 
GiBBS,  who  has  been  unable  to  obtain  an  alkaloid  from  the 
rattlesnake  (Crotalus)  venom.  S.  Weir  Mitchell  and 
E.  T.  Rek'HERT  likewise  state  that  they  have  been  utterly 
unable  to  substantiate  Gautier's  statements.  Still  more 
recently  AVolfexdex,  in  an  elaborate  paper  on  the  nature 
of  cobra  venom,  has  confirmed  Wolcott  Gibbs  as  to  the 
entire  absence  of  any  alkaloidal  body. 


286  LEUCOMAINES. 

Mitchell  and  Reichert  have  made  a  careful  study  of 
the  venoms  of  various  serpents,  such  as  cobra,  rattlesnake, 
moccasin,  and  Indian  viper,  and  have  succeeded  in  isolating 
two  proteid  constituents,  one  belonging  to  the  class  of 
globulins  and  the  other  to  the  peptones.  According  to 
them,  the  globulin  constituent  consists  of  at  least  three 
distinct  globulins.  They  found  that  boiling  coagulates 
and  destroys  the  globulin  as  a  poison,  but  leaves  the 
venom  peptone  toxically  unchanged,  so  that  the  venom, 
though  still  poisonous,  fails  to  produce  the  characteristic 
local  lesions  due  to  fresh  or  unboiled  venom.  On  the  other 
hand,  Gautier  asserts  that  the  venom  is  not  sensibly 
altered  on  being  heated  to  120°-125°,  and  that  the  toxic 
action  remains  constant  even  when  all  the  proteid  con- 
stituents are  removed,  thus  showing  that  the  toxic  action 
cannot  be  attributed  to  the  albuminoids.  The  venom  pep- 
tone from  the  rattlesnake  or  the  moccasin,  however,  wdien 
injected  into  animals  produced  toxic  effects  which  were 
marked  by  an  oedematous  swelling  over  the  site  of  injection  ; 
the  tumor  was  filled  with  serum,  and  so  also  was  the  sub- 
cutaneous cellular  tissue.  Furthermore,  a  gradual  breaking 
down  of  the  tissues  occurred,  accompanied  by  rapid  putre- 
factive changes  and  a  more  or  less  extensive  slough.  That 
peptones  may  possess  intensely  poisonous  properties  has  been 
showm  to  be  the  case  by  a  number  of  authors,  among  whom 
may  be  mentioned  ScHMiDT-MtJLHEiM,  Hofmeister, 
PoLLiTZER,  and  others.  Brieger  has,  moreover,  demon- 
strated that  the  formation  of  peptones  in  the  process  of 
digestion  is  accompanied  by  the  development  of  a  toxic 
ptomaine  which  he  has  named  peptotoxine. 

The  venom  globulins,  on  the  other  hand,  though  present 
in  less  quantity  than  the  peptones,  induced  the  same  re- 


VENOMS    OF    POISONOUS    SERPENTS.  287 

luurkable  local  effects  seeu  on  inject iou  of  the  pure  venom. 
They  cause  local  bleedings,  destroy  the  coagulability  of  the 
blood,  and  rapidly  corrode  the  capillaries. 

Those  results  of  Mitcheij.  and  Rekjhert,  which 
are  given  here  somewhat  in  full,  have  been  questioned  by 
WoLFENDEN,  wlio,  whilst  agreeing  in  the  main  that 
the  poisonous  property  of  venom  is  due  to  proteid  con- 
stituents, regards  their  peptone  not  as  a  true  peptone,  but 
rather  as  one  or  more  bodies  of  the  albumose  group  of  pro- 
teids.  He  likewise  rerards  the  o-lobulin  of  moccasin  venom 
to  be  some  other  proteid  body.  According  to  him,  the 
cobra  venom  owes  its  toxicity  to  the  proteids,  globulin, 
serum-albumin,  acid  albumin.  Occasionally  there  seem 
to  be  present  traces  of  peptone  and  of  hemialbumose. 

In  view  of  this  evidence  of  the  poisonous  nature  of  some 
proteids,  and  of  the  absence  of  true  alkaloidal  bodies, 
Brieger  thinks  it  inadmissible  to  consider  globulins  and 
peptones  as  the  toxic  principles  of  venoms.  He  is  appa- 
rently inclined  to  believe  that  their  action  is  due  to  animal 
alkaloids  on  the  ground  that  these  bases  are  extremely 
soluble,  and  hence  always  go  into  solution  along  with  the 
likewise  very  soluble  proteid  constituents,  and  that  the  diffi- 
culty in  their  isolation  lies  in  the  elimination  of  these 
proteids. 

Cloez  and  Gratiolet  in  1852  examined  the  poison 
contained  in  the  cutaneous  pustules  of  some  batrachians, 
and  succeeded  in  extracting  a  substance  which  gave  a  white 
precipitate  with  mercuric  chloride  and  formed  a  platinum 
double  salt.  Beyond  this  meagre  information  very  little  is 
known  in  regard  to  the  character  of  these  poisons,  though 
Zalesky,  in  1866,  announced  the  isolation  of  an  alkaloid 
to  which   he  assigned  the  formula  C3^HgyN205,  and  which 


288 


LEUCOMAINES. 


he  named  samandarine.  According  to  Calmeil,  the  poison 
from  the  toad  contains  methyl-carbylamine  and  isocyanacetic 
acid. 

Table  of  Leucomaines. 


Formula 

Name. 

Discoverer. 

Source. 

Physiological  action. 

C5  H5  N5 

Adenine. 

Kossel. 

Nuclein-contain- 
ing  organs. 

Non-poisonous ;  muscle 
stimulant. 

C5  H4  N4  0 

Hypoxanthine. 

Srherer. 

Nuclein-contain- 
ing  organs. 

yon-poisonous;  muscle 
stimulant. 

C5  H5  N5  0 

Guanine. 

TJnger. 

Nuclein-contain- 
ing  organs, 
guano. 

Non-poisonous ;  muscle 
stimulant. 

C5  H4  N4  O2 

Xanthine. 

Marcet. 

Nuclein-contain- 
ing  organs, 
calculi. 

Non-poisonous;  muscle 
stimulant. 

Ce  He  K4  O2 

Heteroxanthine. 

Salomon. 

Urine. 

C;  Hg  N4  0., 

Paraxanthine. 

Thudichura. 
Salomon. 

C7  Hg  N4  O3 

Carnine. 

Weidel. 

Liebig's  meat 
extract. 

Non-poisonous ;  muscle 
stimulant. 

C4  H5  N5  0 
C2H5N 

Pseudoxanthine(?) 
Spermine. 

Gautier. 
Schreiner. 

Muscle. 
Spernia,  in  tis- 
sues of leuco- 
cythEemics. 

C5  Hg  N4  0 

Cruso-creatinine. 

Gautier. 

Muscle. 

C5  H10N4  0 

Xantho-creatinine. 

" 

" 

Poisonous. 

C9  H19N7  O4 

Amphi-creatine. 

" 

" 

CnU24Nio05 

C7   H12N4  Oo 

Unnamed. 

Pouchet. 

Urine. 

C3  H5  NO2 

** 

CHAPTER  yill. 

THE  PATHOLOGICAL  IMPORTANCE  OF  THE  LEUCOMAINES. 

"While  the  medical  profession  has  been  giving  mnch 
time,  attention,  and  energy  in  recent  years  to  tlie  stndy  of 
infections  diseases,  it  has  too  much  neglected  a  large  and 
important  class  of  ailments  which  arise  within  the  body 
itself,  and  which  may  be  called  autogenous.  It  is  true, 
without  exception,  so  far  as  we  know,  that  the  excretions 
of  all  living  things,  plants  and  animals,  arc  poisonous  to 
the  organisms  which  excrete  them.  A  man  may  drink  only 
chemically  pure  water,  eat  only  that  food  which  is  free  from 
all  adulteration,  and  breathe  nothing  but  the  purest  air, 
free  from  all  organic  matter,  both  living  and  dead,  and  yet 
that  man's  excretions  would  contain  poisons.  Whence  do 
these  poisons  originate?  They  are  formed  within  the  body. 
They  originate  in  the  metabolic  changes  by  which  the  com- 
plex organic  molecule  is  split  up  into  simpler  compounds. 
We  may  su])pose — indeed,  Me  have  good  reasons  for  believ- 
ing— that  the  proteid  molecule  has  certain  lines  of  cleavage 
along  which  it  breaks  when  certain  forces  are  applied,  and 
that  the  resulting  fragments  have  also  lines  of  cleavage  along 
which  they  break  under  certain  influences,  and  so  on  until 
the  end-products,  urea,  ammonia,  water,  and  carbonic  acid 
gas,  are  reached  :  also  that  some  of  these  intermediate  frag- 
ments are  highly  poisonous  compounds  has  been  abundantly 
demonstrated.  The  fact  that  the  hydrocyanic  acid  molecule 
is  a  frequent  constituent  of  the  leucomaines,  as  has  been 
shown  in  the  preceding  pages,  is  one  of  great  significance. 

25 


290  LEUCOMAINES. 

We  know  that  chemical  composition  is  an  indication  of 
physiological  action,  and  the  intensely  poisonous  character 
of  some  of  the  leucoraaiues  conforms  to  this  fact.  It 
matters  not  whether  the  proteid  molecule  be  broken  up  by 
organized  ferments,  germs,  or  by  the  unorganized  ferments 
of  the  digestive  juices,  or  by  those  still  unknown  agencies 
which  induce  metabolic  changes  in  all  the  tissues — in  all 
cases  poisons  are  formed.  These  poisons  will  differ  in 
quality  and  quantity  according  to  the  proteid  which  is 
acted  upon,  and  according  to  the  force  which  acts,  but  still 
they  will  be  poisonous. 

While  it  is  true  that  germs  are  constantly  present  in  the 
human  intestines,  and  that  they  undoubtedly  act  upon  our 
food,  there  is  no  more  reason  for  believing  that  they  are 
concerned  in  the  actual  production  of  all  the  leucomaines, 
than  there  is  for  believing  that  bacteria  produce  morphine 
in  the  poppy.  The  old  theory,  that  the  chemistry  of  the 
plant  is  altogether  synthetical,  and  the  chemistry  of  the 
animal  altogether  analytical,  has  long  since  been  exploded. 
The  formation  of  carbonic  acid  from  more  complex  mole- 
cules in  the  plant,  and  the  conversion  of  ammonia  into 
urea  in  the  animal,  are  illustrations  from  a  large  class  of 
well-established  facts  which  have  proved  fatal  to  the  old 
theory. 

But  we  shall  not  dwell  upon  the  origin  of  the  animal 
alkaloids,  as  the  time  has  not  yet  come  for  positive  state- 
ments on  the  subject.  We  know  that  they  are  formed  in 
the  body,  that  they  are  contained  in  the  excretions,  and  that 
any  disturbance  between  the  rate  of  their  formation  and 
their  excretion  is  followed  by  a  corresponding  disturbance 
of  the  health. 

In  the  first  place,  although  peptones  cannot  be  classed 
with  alkaloidal  bodies,  they  represent  the  first  known  step 


PATHOLOGICAL    IMPORTANCE.  291 

in  the  breaking  up  of  the  proteid  molecule,  and  a  word 
concerning  their  physiological  effects  may  not  be  out  of  place. 
When  injected  directly  into  the  circulation,  peptones  act  as 
powerful  poisons.  They  destroy  coagulability  of  the 
blood,  lower  blood-pressure,  and,  in  large  quantities,  cause 
speedy  death.  In  health  the  peptones  formed  during  di- 
gestion do  not  reach  the  general  circulation.  In  the 
liver  they  are  robbed  of  their  poisonous  properties  by  being 
converted  into  globulin.  But  it  is  altogether  probable  that 
at  times  the  liver  partially  fails  in  this  function,  and  that 
the  health  suffers  in  consequence.  This  may  be  due  to  the 
taking  of  excessive  quantities  of  proteids,  the  digestion 
being  active  and  the  peptones  formed  and  poured  into  the 
portal  circulation  faster  than  the  liver  can  convert  them  into 
globulin  ;  or  it  may  be  that  from  lack  of  exercise  or  other 
reason  the  liver  is  tardy  in  its  action,  or  "  torpid  "  as  we 
say,  and  small  quantities  of  peptones  pass  into  the  general 
circulation.  The  lassitude,  depression,  sense  of  weight  in 
the  limbs,  and  dulness  in  the  head  occurring  in  the  well- 
fed,  inactive  man  after  his  meals,  Bruxtox  attributes  to 
poisoning  with  peptones.  The  remedy  is  less  food,  espe- 
cially less  nitrogenous  food,  and  more  exercise.  That  some 
substance  resulting  from  the  proteids  of  the  food  is  the 
cause  of  this  trouble,  Beuxton  thinks  is  evidenced  by  the 
fact  that  "  the  weakness  and  languor  are  apparently  less 
atter  meals  consisting  of  farinaceous  food  only." 

Briegee  obtained  by  digesting  fibrin  with  gastric  juice 
a  substance  which  gives  reactions  with  many  of  the  general 
alkaloidal  reagents,  and  to  which  he  has  given  the  name 
peptotoxine.  A  few  drops  of  a  dilute  aqueous  solution  of 
this  substance  sufficed  to  kill  frogs  within  fifteen  minutes. 
The  frogs  became  apparently  paralyzed  and  did  not  respond 
to  stimuli.     Slight  tremor  was  perceptible  in  the  muscles 


292  LEUCOMAINES. 

of  the  extremities.  Rabbits  of  about  one  kilogram  weight 
were  given  from  0.5  to  1  gram  of  the  extract  subcuta- 
neouslj.  About  fifteen  minutes  after  the  injection,  gradual 
paralysis  set  in  in  the  posterior  extremities:  the  animal  fell 
into  a  soporific  condition,  sank  and  died.  In  some  rabbits 
several  hours  elapsed  before  the  above-mentioned  symptoms 
appeared. 

Peptotoxine  was  also  found  by  Brieger  as  one  of  the 
first  putrefactive  products  of  proteids,  as  fibrin,  casein, 
brain  substance,  liver,  and  muscle.  But  after  putrefaction 
had  continued  for  eight  days  or  longer,  peptotoxine  disap- 
peared. 

It  is  highly  probable  that  many  of  the  nervous  symp- 
toms which  accompany  dyspepsia  are  due  to  the  formation 
and  absorption  of  poisonous  substances. 

In  some  persons  the  tendency  to  the  formation  of  poisons 
out  of  certain  foods  is  very  marked.  Thus,  there  are  some 
to  whom  the  smallest  bit  of  egg  is  highly  poisonous  ;  with 
others,  milk  will  not  agree ;  and  instances  of  this  kind  are 
sufficiently  numerous  to  give  rise  to  the  adage,  "  What  is 
one  man's  meat  is  another  man's  poison." 

Brunton  is  of  the  opinion  that  the  condition  which  we 
term  "  biliousness,"  and  which  is  most  likely  to  exist  in 
those  who  eat  largely  of  proteids,  is  due  to  the  formation 
of  poisonous  alkaloids. 

We  will  venture  the  assertion  that  ordinary  colds  are 
best  explained  by  the  supposition  that  certain  effete  matters, 
which  are  normally  excreted  by  the  skin,  are  retained. 
This  is  borne  out  by  the  effects  on  the  nervous  system,  and 
by  the  fact  that  the  only  successful  methods  of  treatment 
are  essentially  eliminative. 

That  certain  febrile  conditions  are  autogenous  there  can 
scarcely  be  a  doubt.     These,  like  other  diseases  originating 


PATHOLOGICAL    IMPORTANCE.  298 

within  the  system,  may  be  due  to  either  of  the  following 
causes :  (1)  There  may  be  an  excessive  formation  of  poi- 
sons in  the  body.  Thus,  Bouchard  has  shown  that  the 
urine  excreted  during  the  hours  of  activity  is  much  more 
toxic  than  tliat  excreted  during  tlie  hours  of  rest.  Both 
physical  and  mental  labor  are  accompanied  by  the  forma- 
tion of  these  poisonous  substances,  and  if  the  hours  of  labor 
are  prolonged  and  those  of  rest  shortened,  there  will  be  an 
accumulation  of  effete  matters  within  the  system.  (2)  The 
accumulation  of  the  poisonous  matters  may  be  due  to  defi- 
cient elimination. 

First,  we  may  mention  fatigue  fever,  which  is  by  no 
means  uncommon,  and  from  which  the  busy  physician  not 
infrequently  suffers.  One  works  night  and  day  for  some 
time ;  elimination  seems  to  proceed  normally ;  but  after  a 
few  days  there  is  an  elevation  of  temperature  of  from  one 
to  three  degrees,  the  appetite  is  impaired,  and  then  if  the 
opportunity  for  rest  is  at  hand  sleep  is  impossible.  The 
tired  man  retires  to  his  bed  expecting  to  fall  asleep  im- 
mediately, but  he  tosses  from  side  to  side  all  night,  or  his 
sleep  is  fitful  and  unrefreshing.  The  brain  is  excited  and 
refuses  to  be  at  rest. 

Fatigue  fever  is  frequently  observed  in  armies  upon 
forced  marches,  especially  if  the  troops  are  young  and  raw. 
Mosso  has  recently  studied  this  fever  in  the  Italian  army. 
He  states  that  in  fatigue  the  blood  is  subjected  to  a  process 
of  decomposition  brought  about  by  the  infiltration  into  it 
from  the  solid  tissues  of  poisonous  substances,  which  when 
injected  into  the  circulation  of  healthy  animals  induce 
malaise  and  all  the  signs  of  excessive  exhaustion. 

This  fever  is  sometimes  pronounced  malarial,  and  quinine 
is  administered,  but  it  does  no  good,  often  harm  by  increas- 

25* 


294  LEUCOMAIXES. 

iDg  cerebral  excitement.  The  proper  treatment  is  prolonged 
rest. 

Then  there  is  the  fever  of  exhaustion,  which  differs  from 
fatigue  fever  only  in  degree.  It  is  brought  on  by  pro- 
longed exertion  without  sufficient  rest  and  often  without 
sufficient  food.  The  healthy  balance  between  the  formation 
and  excretion  of  poisons  is  disturbed,  and  it  may  be  weeks 
before  it  is  reestablished — indeed,  it  may  never  be  reestab- 
lished, for  some  of  these  cases  terminate  fatally.  The  fever 
of  exhaustion  may  take  on  the  typhus  form,  delirium  may 
appear,  muscular  control  of  the  bowels  may  be  lost,  and 
death  may  result. 

Between  these  extremes  of  fatigue  fever  and  the  fever  of 
exhaustion  there  may  be  every  degree  of  fever  from  over- 
exertion. Then  again,  there  is  the  fever  of  non-elimina- 
tion, which  all  physicians  of  experience  have  observed. 
There  is  a  feelino;  of  languor,  the  head  aches,  the  tonsfue  is 
coated,  the  breath  offensive,  and  the  bowels  constipated. 
The  physician  fears  typhoid  fever,  but  finds  that  a  good, 
brisk  cathartic  dissipates  all  the  unpleasant  symptoms,  and 
the  temperature  falls  to  the  normal.  This  fever  is  also 
liable  to  appear  amoug  those  who  are  confined  to  bed 
from  other  causes.  Bruntox  says :  "  jN^o  one  who  has 
watched  cases  of  acute  disease,  such  as  pneumonia,  can 
have  failed  to  see  how  a  rise  of  temperature  sometimes 
coincides  with  the  occurrence  of  constipation,  and  is  re- 
moved by  opening  the  bowels."  The  surgeon  and  obstetri- 
cian have  often  had  cause  to  rejoice  when  they  have  found 
a  fever  which  they  feared  indicated  septicsemia  disappearing 
after  free  purgation. 

BouCHAED  has  shown  that  normal  f?eces  contain  a 
highly  poisonous  substance  which  may  be  separated  from 
them  by  dialvsis,  and  which,  when  administered  to  rabbits, 


I.— Tahular  Vikw  of  TKi;  Reactions  of  Certain  Ptom 


Taijle  II. — Ptomaines  in  Toxicological  Examinations. 


'sssr 

"■sr 

Hjdrochlorido, 

°S=- 

l.-ll.™„™ipltiiM 

ssisr 

'"ZSS^ 

"■•ssr- 

K 

SS 

a«L''' 

llBBm- 

"ri^Xi"'.'""'' 

— 

WhLlo  pnajipltiite. 

"S3S- 

'ssr 

'--"■ 

on..,„,,l.l.u 



... 

""■ 

"■ 

TA1II.E  III.— ReACTIOSS  of  SliLMl'a  I'T 


PATHOLOGICAL  IMPORTANCE.       295 

produces  violent  convulsions.  lie  estimates  that  the 
amount  of  poisonous  alkaloids  formed  in  the  intestines  of 
a  healthy  man  each  twenty- four  hours  would  be  quite  suf- 
ficient to  kill  if  it  was  all  absorbed.  He  proposes  the  term 
stercorremia  for  that  condition  which  results  from  arrest  of 
excretion  from  the  intestine. 

It  is  not  supposed  by  any  one  at  present  that  all  the 
symptoms  of  so-called  urreraic  poisoning  result  from  reten- 
tion of  urea  alone,  but  the  urine  contains  substances  a 
thousand-fold  more  poisonous  than  urea,  and  these  also  are 
retained.  We  take  the  amount  of  urea  retained  as  an  evi- 
dence of  the  extent  of  danger,  because  we  can  estimate  the 
amount  of  urea  definitely  just  as  we  take  the  amount  of 
carbonic  acid  gas  in  tiic  air  in  making  an  estimate  of  the 
extent  to  which  it  is  vitiated,  and  not  because  we  believe 
that  either  the  urea  in  the  one  case,  or  the  carbonic  acid  in 
the  other,  is  really  the  dangerous  substance. 

That  the  development  of  infectious  diseases  is  largely 
dependent  upon  the  condition  of  the  person  into  whom  the 
germs  are  introduced  is  well  known.  Two  men  may  drink 
of  the  same  water  infected  with  the  bacillus  of  typhoid 
fever,  and  yet  one  will  have  the  disease,  and  the  other  will 
escape.  The  importance  of  the  personal  equation  in  ac- 
quiring infectious  diseases  is  fully  recognized.  That  the 
difference  in  susceptibility  may  be  due  to  the  relation 
between  the  formation  and  excretion  of  these  poisons 
generated  within  the  body,  we  tiiink  higiily  probable. 


CHAPTER   IX. 

bibliography. 

Ptomaines. 

AiTKEN,  Wm.    On  the  Animal  Alkaloids.    Lond.  and  Phila.,  1887. 
Albertoni  e  Lussana.     Sulla  velenosita  degli   estratti   cada- 
veric!.    Bergamo. 
Allaben.     New  York  Med.  Eecord,  1886. 
Anrep,  B.  v.    St.  Petersb.  med.  Woctiensclir.,  8,  35, 1883.  Deutscli. 

med.  Ztg.,  1884,  5. 
Arnold,  0.     ArcMv.  d.  Pharm.,  221,  435,  1883;    Cliem.  Jahrb., 

1883,  1357;    Agric.  Cliem.  Jahrb.,  26,  419,  1883;    Deutscli. 

med.  Ztg.,  2,  503,  1884. 
Arnould,  J.     Gaz.  de  Paris,  3,  1882. 
Aubert,  vide  Lepine. 

AuERBACH,  B.     Vierteljahrschr.  f.  ger.  Med.,  N.  F.,  11,  66,  1884. 
Baeyer,  A.     Annal.  d.  Chem.  u.  Pharm.,  140,  306;    142,  322. 

Ber.  d.  Chem.  Gesellsch.,  1883,  1186. 
Balbiano.     Zeitschr.  f.  Anal.  Chem.,  23,  451. 
Balland.     Journ.  de  Pharm.  et  de  Chim.,  12,  341,  1885;    Arch. 

d.  Pharm.,  224,  93,  1886. 
Ballard.     Ninth  Annual  Eeport  of  Local  Gov.  Board. 
Baumann.    Zeitschr.  f.  Physiol.  Chem  ,  1,  60;  10, 123.    Schmidt's 

Jahrb.,  210,  5,  1886.     Ber.  d.  Chem.  Gesellsch.,  9,  54,  1389, 

1715,  1747. 
Baumann  u.  Gergens.     Pfliiger's  Archiv,  12,  205. 
Baumert,  G.     Archiv.  d.  Pharm.,  [3]  25,  911,  1887. 
Baumstark.     Zeitschr.  f.  Physiol.  Chem.,  9,  168. 
Beach,  C.  C.    New  York  Med.  Journ.,  46,  205,  1887. 
Beckurts,  H.      Arch.  d.  Pharm.,  220,   104,  1882.      Schmidt's 

Jahrb.,  195,  9,  1882.     Chem.  Jahrb.,  1882,  1115. 
Bergeron  et  L'Hote.    Compt.  Rendus,  91,  390,  1880.    Rep.  de 

Pharm.,  8,  458.     Archiv.  d.  Pharm.,  219, 132, 1881 ;  221,  416, 

1883. 


PTOMAINES.  297 

Bergmann.  Das  Putride  Gift  iind  die  Putride  Infection.  Dor- 
pat,  1868. 

Bergmann  u.  Schmiedeberg.     Med.  Centralbl.,  1869,  497. 

Beumer  u.  Peifer.     Zeitschr.  fiir  Hygiene,  1. 

BiFFi,  Seraf.     Ann.  Univ.,  223,  497,  1875. 

Billroth.  Untersuchungen  fiber  die  Vegetationsformen  von 
Coccobacteria  septica,  etc.     Berlin,  1874. 

BiscHOF.     Deutsch.  med.  Ztg.,  11,  898,  1885, 

Blankenhorn,  vide  Gamgee. 

Bocci.     Med.  Centralbl.,  1882. 

BOCKLISCH,  0.  Ber.  d.  Chem.  Gesellsch.,  18,  86,  1922;  20,  1441. 
Vide  Brieger,  Ueber  Ptomaine,  III.,  42. 

BoHM.  Arch.  d.  Pharm.,  224,  418, 1886.  Zeitschr.  f.  Zucker  Ind., 
13,  107.  Archiv  f.  Experim.  Pathol.,  19,  87.  Ber.  d.  Chem. 
Gesellsch.,  19,  Ref.  37. 

Bollinger.     Ziir  Pathologic  des  Milzbrandes.     Miinchen,  1872. 

Bouchard,  Ch.  Gaz.  Hebdom.,  [2]  23,  13,  1886.  Compt.  Ren- 
dus,  102,  669,  727. 

BouCHARDAT.     Annalcs  d'Hygiene,  17,  360. 

Bouel.     Virchow's  Archiv,  11. 

Boutigny.     Annales  d'Hygiene,  21,  234. 

BOUTMY.    Annal.  d'Hygiene  piibl.,  [3]  4,  193,  1880.     Vide  Brou- 

ARDEL. 

Brieger,  L.  Ueber  Ptomaine,  I.,  II.,  III.,  Theile,  Berlin,  1885- 
1886.  Ber.  d.  Chem.  Gesellsch.,  16,  1186,  1405;  17,  415,  515, 
1137,2741;  18,1922;  20,  Ref.  67,  68,  656,  797.  Zeitschr.  f. 
Physiol.  Chem.,  3,  135;  7,  274;  8,  9,  1;  11,  184.  Zeitschr.  f. 
Anal.  Chem.,  22,  638.  Verhandl.  d.  Physikal.  Gesellsch.  zu 
Berlin,  1882-83.  Deutsche  med.  Wochenschr.,  1885,  1887, 
303.  Berlin,  klin.  Wochenschr.,  21,  No.  14;  23,  18 ;  24,  817; 
April  23,  1888.  Zeitschr.  f.  klin.  Med.,  3,  Heft  3 ;  10,  Heft  3 ; 
11,  Heft  2,  3.  Deutsche  med.  Ztg.,  11,  429,  747,  1885;  1883, 
497  ;  1886,  472.  Fortsch.  d.  Med.,  2,  434.  Archiv  f.  Anat.  u. 
Physiol.,  1883,  277.  Agr.  Chem.  Jahrb.,  1883,  26, 419.  Archiv 
d.  Pharm.,  221,  370;  223,  193.  Chem.  Jahrb.,  1883,  1359. 
Centralbl.  f.  Bacteriologie,  1,  662,  1887. 

Brieger  u.  Ehrlich.     Berliner  klin.  Wochenschr.,  1882,  No.  44. 

Brouardel,  p.,  et  Boutmy,  E.  Bull.  d.  I'Acad.,  [2]  10,  588, 1881. 
Compt.  Rendus,  92,  1056.    Ann.  d'Hyg.  publ.,  [3J  5,  497, 1881. 


298  BIBLIOGRAPHY. 

Gaz.  de  Paris,  20,  284, 1881.  Schmidt's  Jahrb.,  191,  11, 1885. 
Chem.  Jahrb.,  1881,  975.  Eep.  de  Pharm.,  8,  406,  1880;  276, 
1881.  Archiv.  d.  Pharm.,  219,  396,  462, 1881.  Monit.  Scientif., 
[3]  2,  732,  736,  738.  Chem.  Jahrb.,  1881, 1058.  Annal.  d'Hy- 
giene,  6,  9,  1881.  Ann.  d'Hyg.  publ.  et  de  Med.  legale,  [3]  4, 
253,  335,  1880.  Archiv.  d.  Pharm.,  219,  462,  1881;  221,  404, 
1888.  Schmidt's  Jahrb.,  191,  11,  1881.  Eep.  de  Pharm.,  26, 
404,  1879. 

Brown,  Adrian  J.    Journ.  Chem.  Soc,  1886. 

Brtjgnatelli  et  Zenoni.  Journ.  de  Med.  et  de  Chim.,  [4]  78, 
41,  1877.     Ber.  d.  Chem.  Gesellsch.,  9,  1437. 

Brunton,  T.  Lauder.     Practitioner,  25,  349,  1880;  30,  1885. 

BuCHHEiM,  E.    De  trimethylamino.    Inaug.  Dissertation.   Dorpat. 

BucHMAiSTN-.     Chem.  Centralbl.,  1884,  975. 

BuCHNER.     Toxicologic,  1829. 

BuJWiD.     Ber.  d.  Chem.  Gesellsch.,  1883,  432. 

Cadeac  et  Malet.  Compt.  Eendus,  103,  398.  Ber.  20,  Ref. 
437. 

Cadet  de  Gassicourt.     Journ.  de  Pharm.     Orfila,  Traite,  etc. 

Cantani.     Deutsch.  med.  Wochenschr.,  1886,  No.  45. 

Capitan  et  Charrin.    Soc.  de  Biol.,  862,  1882. 

Casali,  a.     Eiv.  clinic,  6,  331,  1881.     Gazz.  chim.  ital.,  11,  314, 

1881.  Chem.  Jahrb.  1881,  975.     Schmidt's  Jahrb.,  195,  9, 

1882.  Archiv.  d.  Pharm.,  221,  69,  485,  540,  1883.  Annal.  d. 
Chim.,  1882.  Ann.  di  Chim.  appl.  alia  Pharm.  ed  alia  Med., 
1883, 147.  Ann.  Univers.,  261,  32, 1882.  Ann.  di  Chim.,  188, 
89,  147,  1883. 

Charrin,  vide  Rogers,  also  Capitan. 

Christison.     a  Treatise  on  Poisons,  1845. 

Ciotto.     Parte  chimica  di  un  caso  di  perizia  per  sospetto  vene- 

ficio.     Padova,  1880. 
Cloez.     Journ.  f.  Prakt.  Chem.,  1853,  468. 
Coldstream.     Christison  on  Poisons. 
Colin.     Compt.  Rend.,  1876,  1880. 
Combe.     Edinburgh  Med.  and  Sur.  Journ.,  29,  1888. 
Coppola,  F.     Gazz.  chim.  ital.,  12,  511;    13,11,1883;    14,  124. 

Chem.  Jahrb.,  1883,   1357.     Agric.  Chem.  Jahrb.,  26,  419, 

1883.  Arch.  ital.  de  Biolog.,  4,  63,  1883.  Gazz.  chim.  ital., 
13,  11.     Fortschr.  d.  Med.,  2,  53,  1884.     Journ.  Chem.  Soc, 


PTOMAINES.  299 

43,  522.     Chem.  Zeit.,  7.  204.     Yearbook  of  Pharmacy,  1885, 
p.  110. 
Corona,  vide  Gianetti. 

CoiiRE.     Archiv.  de  Physiol.,  norm,  et  pathol.,  4,  405. 
CoRTEZ.     Dragendorff's  Jahrb.,  1878,  615. 
CuRTMAN,  C.  0.     Pharm.  Rundschau,  5.  275,  1887. 
CzuMBETiTZ.     Pharm.  Post.,  14,  47.     Arch.  d.  Pharm.,  219,  63, 
1881.     Bull,  de  I'Acad.,  [2]  15,  2P>9,  270,  303,  345,  390,  425, 
1886. 
Dann.     De  Veneni  Bolulini  Viribus  et  Natura,  1882. 
Davaine.     Compt.  Rend.,  57  and  67. 
De  Bary.     Vorlesungen  iiber  Bakterien,  1885. 
De   Brehm,   H.     Sur   la  mycose   septique.     These    inaugurale. 

Dorpat. 
De  Coninck,  Oechsner,  et  Pinet.     Soc.  de  Biol.,  1882;  1885, 

108. 
De  Pietra  Santa.     Journal  d'Hygiene,  30  Juin,  1881. 
De  Raison,  W.     Notes  experimentales  relatives  a  la  connaissance 

de  I'intoxication  putride.     These  inaugurale.     Dorpat. 
Delafond.     Traite  sur  la  maladie  de  sang  des  betes  a  laine,  1843. 
Dessaignes.     Chem.  Jahresb.,  1851,  481 ;    1857,  382-     Annal.  d. 

Chem.  u.  Pharm.,  100,  218. 
DiAKONOW.     Tiibingen,  Med. -chem.    Untersuch.,   Heft   2,   1867. 
Centralbl.  f.  med.  Wissensch.,  1868,  Nos.   1,   7,  28.     Chem. 
Jahresb.,  1867,  776  ;  1868,  730. 
Di  Mattel     Centralbl.  f.  med.  Wissensch.,  1868,  Nos.  1,  7,  28. 
Chem.  Jahresb.,  1868,  730;  1867,  776.     Arch.  p.  1.  Sci.  med., 
6  F.  3,  245,  1882. 
Dragendorff.      Die  Gerichtliche  Chemische  Ermittelung   der 
Gifte,  1876.      Beitriige   zur  Gerichtlichen   Chemie   einzelner 
Organischer  Gifte,  Petersburg,  1872.     Arch.  d.  Pharm.,  221, 
415,  1883. 
DuCLAUX.     Compt.  Rondus,  101,  1885. 
DuPETiT.     Compt.  Rendus,  95,  1367.     Rep.  de  Pharm.,  11,  125. 

Arch.  d.  Pharm.,  221.  462,  1883. 
DuPRE,  vide  Jones,  Bence.     Magendie's  Journ.  de  Phys.,  3,  72, 

1823. 
DuPUY,  M.     Arch.  gen.  de  Med.,  11,  297,  1826. 
DuPUY  ET  Trousseau.    Arch.  gen.  de  Med.,  11,  373,  1826. 


300  BIBLIOGRAPHY. 

Eberth.     Virchow's  Archiv,  81. 

Eheenberg,  E.     Zeitschr.  f.  Physiol.  Chem.,  U,  145,  438,  239; 

12,  145.     Ber.  d.  Chem.  GeselL,  20,  Ref.  629,  656.     Journ.  f. 

Prakt.  Chem.,  36,  117. 
Ehrhaedt.     Schmidt's  Jahrb.,  213,  248. 
Ehrlich.      Das  Sauerstoffbediirfniss   des  Organismus.      Berlin, 

Hirschwald,  1885. 
Etard,  vide  Gautier. 
Fassbender,  vide  Rorsch. 
Fayrer,  J.     British  Med.  Journ.,  1884,  205.     Fortschr.  d.  Med., 

2,  314,  1884. 
Fehleisen.     Arbeiten  a.  d.  Chirurg.  Klinik   d.   Univ.  Berlin, 

III.  Theil. 
Felletas,  E.     Pester  med.  Chir.  Presse,  10,  1874. 
Feltz  u.  Ehrmann.     Acad,  de  Med.     Ber.  d.  Chem.  Gesellsch., 

20,  Eef.  437. 
Feltz  u.  Ritter.    Acad,  de  Med,,  1881-1884.    Ber.  d.  Chem. 

Gesellsch.,  20,  Ref.  437. 
Feser.     Jahrb.  von  Virchow  u.  Hirsch,  1876.  . 
Firth.    London  Lancet,  1887,  1. 
FiTZ.     Ber.  d.  Chem.  Gesellsch.,  1882  u.  1884. 
Fletcher,  A.    Amer.  Journ.  Med.  Sciences,  1883, 131.    Fortschr. 

d.  Med.,  2,  133,  1884. 
Fliess.     Archiv.  f.  Anat.u.  Phys.,  1882,  HI;    1883,190.     Inaug. 

Dissertation.     Berlin,  Leipzig,  1883. 
FODERE.     Medecine  legale,  IV.,  85. 
Frank,  B.    Ber.  d.  Botan.  Gesellsch.,  3,  1885. 
Gamgee  and  Blankenhorn.     Journ.  of  Physiol.,  2,  113.     Ber. 

d.  Chem.  Gesellsch.,  12,  1229. 
Garnier,  S.    Ann.  d'Hyg.  publ,  [3]  9,  78, 1883.    Union  Pharm., 

1883,  216. 
Gaspard,  B.    Magendie's  Journ.  de  Physiol.,  2, 1, 1822 ;  4, 1, 1824. 
Gautier,  A.    Monit.  Scientif.,   [3]  11,  736,  738,  1881.     Chem. 

Jahrb.,   1881,   1059.     Journ.  de  I'anat  et  physiol.,  17,  333, 

1883.     Bull,  de   I'Acad.  de  Med.,  20,  620,  1881.     Arch.  d. 

Pharm.,  219,  396,  1881 ;  221,  483 ;  223,  513,  1883.     Compt. 

Rendus,  94,  1119,  1298.     Chem.  Jahrb.,  1882,  1116.    Agric. 

Chem.  Jahrb.,  25,  428,  1882.     Rev.  d.  Naturw.,  1883,  576. 

Monit.  Scientif.,  [3]  12,  422,  1882.     Rep.  d.  Pharm.,  9,  278, 


PTOMAINES.  301 

1881.    Gaz.  Med.,  [2]  23,  483,  1881.     Bull.  Soc.  Chim.,  43, 
158.     Bull.  d.  I'Acad.,  15,  65,  115,  1886.     Schmidt's  Jahrb., 
210,  8,  1886. 
— .     Sur  les  Alcaloides,     Ptomaines  et  Lcucoraaines.     Paris, 


1886.    Bull,  de  I'Acad.  de  Med..  1886.    Ber.  d.  Chem.  Ge- 
sellsch.,  20,  Ref.  337. 
Gadtier,  a.,  et  Etard,  A.     Gaz.  de  Paris,  27,  337,  1882.     Bull. 
Soc.  Chim.,  37,  305,  1882.     Schmidt's  Jaiirb.,  195,  10,  196, 

1882.  Chem.  Centralbl.,  1882.  Rev.  d.  Xaturw.,  1883,  576. 
Compt.  Rendus,  94,  973,  1357,  1598,  1601,  1882 ;  97,  263,  325. 
Monit.  Scientif.,  [3J  12,  694.  Chem.  Jahrb.,  1882,  1236. 
Arch.  d.  Pharm.,  221,  485.  Agric.  Chem.  Jahrb.,  26,  419, 

1883.  Zeitschr.  f.  Anat.  Chem..  21,  623. 
Geiseler.     Ruat's  Magazine,  16,  111. 
Gergens,  vide  Baumanx. 

Gerlach.     Magazin  f.  Thierheilkunde. 

GlACOMELLi,  L.  Zeitschr.  d.  Oesterr.  Apothekervereins,  1884. 
Archiv.  d.  Pharm.,  222,  290,  1884.  Agric.  Chem.  Jahrb.,  27, 
688,  1884.     Deutsch.  med.  Ztg.,  1884,  131.  ; 

GiANETTi  E  Corona.  Sugli  aicaloidi  cadaverici  o  ptomaine 
del  Selmi.     Bologna,  1880.     Arch.  d.  Pharm.,  219,  198. 

Gibson.     New  York  Med.  Record,  1886,  2. 

Glause  u.  Luchsixger.     Fortschr.  d.  Med.,  2,  276,  1884. 

Grabner,  F.  Beitriige  zur  Kenntniss  der  Ptomaine.  Inaug. 
Dissertation.     Dorpat,  1882. 

Gram,  Ch.  Archiv.  f.  Experim.  Pathol.,  20,  116.  Ber.  d.  Chem. 
Gesellsch  ,  19,  Ref.  503. 

Grawitz.     Virchow's  Archiv,  110,  1. 

Griesixger.     Infectionskrankheiten,  p.  320,  1885. 

GuARESCHi.  Annal.  di  Chim.  e  Farmacol,  1887,  237.  Archiv.  d. 
Pharm.,  [3j  26,  83,  1888. 

GuARESCHi  ET  MoxARi.     Riv.  di  Chim.,  [3]  2,  190,  1884. 

GCARESCHI  ET  Mosso.  Les  Ptomaines,  Turin,  1883.  Arch.  ital. 
de  Biol.,  2,  367,  1882,  1883.  Ber.  d.  Chem.  Gesellsch.,  1876, 
197;  17,  84.  Gaz.  chim.  ital.,  13,  493,  538,  1883.  Riv.  chim. 
med.  farm.,  1,  54,  92,  191.  Journ.  f.  Prakt.  Chem.,  [2]  27, 
425;  28,  504.  Chem.  Jahrb.,  1883,  1357.  R.  Acad.  d.  Lincei, 
1882.     Journ.  Chem.  Soc,  44,  1156 ;  45. 

GussENBAUER.  Scpthsemie,  pyohtemie,  and  pyosepthaemie.  Stutt- 
gart, 1882. 

26 


B02  .BIBLIOGRAPHY. 

PIager.     Pharm.  Centralhalle,  15,  16.      Arch.  d.  Pharm.,  221, 

405,  1888. 
Haitinger.     Monatsbl.  f.  Chem.,  3,  688. 
Haller.     Physiologie,  Bd.  III.,  154. 

Harkawy.     Ueber  Basische  Fauliiissprodukte.     Inaug.  Disser- 
tation.    Strassburg,  1877. 
Harnack.    Chem.    Jahresb.,    1876,   803.      Archiv.   f.   experim. 

Pathol,  u.  Pharmak.,  4,  168.     Vide  Schmiedeberg. 
Hasebroek,  K.     Zeitschr.  f.  Physiol.  Chem.,  12,  148,  1888. 
Heckel.     Compt.  Eendus,  102,  1317. 
Hemmer.     Experimentelle  Studien  iiber  die  wirkung  Faulender 

Stoflfe  auf  den  Thierischen  Organismus.     Miinchen,  1866. 
Henkemann.     Hufeland's  Journal,  57,  2,  106. 
Hermanides,  F.  E.     Nederl.  Weekbl.,  1886,  10. 
Hesse.     Chem.  Jahresb.,  1857,  403;    1861,500.     Journ.  f.  Prakt. 

Chem.,  71,  471.     Ann.  d.  Chem.  u.  Pharm.,  119,  368. 
Heusinger.      Die   Milzbrandkrankheiten    der  Thiere   und   des 

Menschen. 
HiLLER.     Die  Lehre  von  die  Faulniss.     Berlin,  1879.     Centralbl. 

f.  Chiriirg.,  1876. 
HocKSiNGER.     Centralblatt  fur  Bakteriologie,  1887. 
HoFFA.     Die  Natur  des  Milzbrandsgiftes.     Wiesbaden,  1886. 
HOFMANN,  A.  W.     Zeitschr.  f.  ger.  Med.,  N.  F.  13,  1,  1870.    Ber. 

d.  Chem.  Gesellsch.,  4,  666. 
HOPPE  Seyler.     Handbuch  d.  Phys.  u.  Pathol.  Chem.  Analyze. 

5te  Aufgabe.     Ber.  d.  Chem.  Gesellsch.,  12,  702,  2251. 
HuEPPE,  F.     Deutsch.  med.  Wochenschr.,  1884,  Nos.  48-50. 
HuGOUNENQ,  L.     Les  alcaloides  d'origine  animale.     Paris,  1886. 
HuNDESHAGEN,  F.     Journ.  f.  Prakt.  Chem.,  28,  345. 
HuNNEFELD.     Hom's  Archiv,  1827. 
HuSEMANN,  Th.     Arch.  d.  Pharm.,  216,  169;  217,  327;  219,  187, 

204,  415,  424 ;   220,  270 ;   221,  481 ;  222,  521, 1884.     Schmidt's 

Jahrb.,  186,  123;    191,6.     Chem.  Jahrb.,  1881,  975;    1882, 

1116,  221,  401;  1883,  1357.     Chem.  News,  1882. 
Jacobson.     Chem.  Centralbl.,  87,  1295. 
Jahks,  E.     Ber.  d.  Chem.  Gesellsch.,  18,   2520;    20,  Ref,  576. 

Chem.  Centralbl.,  87,  1082.     Archiv.  d.  Pharm.,  [3]  25,  479. 
Jeannel.     Deutsch.  med.  Ztg.,  11,  379,  1885. 
Jeanneret.     Untersuchungen  iiber  die  Zersetzung  von  Gelatine 


PTOMAINES.  303 

und  Eiweiss  durch  die  geronnten  Pankreasfermente  bei  Luft- 

abschluss.     Leipzig,  1877. 
.ToFFROY,  A.     Arch.  Physiol.,  188G,  800. 
Jones,  Bence  H.  and  Dupre.     Med.  Times  and  Gaz.,  Aug.  18, 

163,  1866.    Schmidt's  Jahrb.,  132,  4, 1866.    Zeitschr.  f.  Chem. 

u.  Pharm.,  1866.     Pharm.  Centraihalle,  16,  No.  10.     Ber.  d. 

Chem.  Gesellsch.,  1874,  1491. 
Kausch.     Ueber  den  Milzbrand  des  Rindviehes,  1805. 
Kellner,  0.  u.  Yo.sHii,  T.     Zeitsrhr.  f.  Pliysiol.  Chem.,  12,  95, 

1888. 
Kerner.     Nouvelles  Observations  siir  les  Empoisonments  mor- 

tels  qui  arrivent  si  souvent  dans  le  Wurtemburg  par  I'usage 

des  Boudins  fumees.     Tiibingen,  1820. 
Klebs.     Allgemeine  Pathologic,  p.  874. 
Kobert,  R.     Schmidt's  .Tahrb.,  189,  219;  201,  1,  1884;   186,  123, 

1880;  196,  6,  1882  ;  195,  8,  1884.     Archiv.  f.  Experim.  Pathol. 

u.  Phurmalc,  18,  816. 
Koch,  R.     Mittheilungen  aus  dem  kaiserl.  Gesuudheitsamt,  1881, 

Bd.  I.     Berlin,  klin.  Wochenschr.,  1884,  1885. 
Koch,  W.     Milzbrand  u.  Rauschbrand.     Stuttgart,  1886. 
KOPPE.     Chem.  Jahresb.,  1870,  876.     Vide  Schmiedeberg. 
Korbrich,  a.     Chem.  Zeit.,  4,  196,  1881 ;   5,  196,  1882.     Rep.  de 

Pharm.,  26,  404,  1879.     Chem.  Jahrb.,  1881,  976. 
Kunz.     Archiv.  d.  Pharm,  223,  701.     Zeitschr.  f.  Anal.  Chem., 

26,  113. 

Laborde.     Soc.  de  Biol.,  1885,  27. 

Ladenburg.     Ber.  d.  Chem.  Gesellsch.,  18,  2956,  8100;  19,  2585; 

20,  2216. 
Ladd,  E.  F.     Fourtii  Annual  Report  of  Board  of  Control  of  the 

New  York  Experiment  Station,  Elmira,  N.  Y.,  p.  818.    Ibid., 

Fifth  Annual  Report,  p.  862. 
Lamouroux.     Orfila's  Toxicologic. 
Lea.     Chem.  Jahrb.,  1862,  831.     Ber.  d.  Chem.  Gesellsch.,  17, 

1137. 
Lebox.     Compt.  Rendus,  1885. 
Lenz.     Zeitschr.  f.  Anal.  Chem.,  21,  622.     Agric.  Chem.  Jahrl)., 

27,  458,  18,S4. 

Leone,  T.     Archiv.  f.  Hygiene,  1886,  168. 

LnpiNE  ET  AuBERT.     Compt.  Rend.,  1885,  1886.     Deutsch.  mcd 
Ztg.,  1886,  117. 


304  BIBLIOGRAPHY. 

Lepine  et  Gueriit.    Eev.  de  Med.,  765,  1884. 

Leuret.     Arch.  gen.  de  Med.,  11,  98,  1826. 

Lewkowitsch.     Ber.  d.  Chem.  Gesellsch.,  1883,  1586,  2722. 

L'HoTE,  vide  Bbrgbros. 

LiEBEEMA:>f]s',  L.     Maly's  Jahresb.  f.  Thier-Chemie,  1885. 

LlEBlG.     Annal.  d.  Chem.  u.  Pharm.,  42,  278. 

LlEBREiCH.  Ber.  d.  Chem.  Gesellsch.,  2,  12;  3,  161.  Anual.  d. 
Chem.  u.  Pharm.,  134,  29. 

LiMLEE.     Centralblatt  fiiir  Bacteriologie,  1888. 

LniPPacHT.     Anual.  d.  Chem.  u.  Pharm.,  101,  296. 

LiPPMA>-x,  E.  vox.     Ber.  d.  Chem.  Gesellsch.,  20,  3201,  1887. 

LoHMEYER.     Virchow's  Archiv,  104,  169. 

LoMBROSO,  C.  Eiv.  Chim.,  [2]  12,  368.  Gaz.  de  Paris,  51,  653, 
1875.  Med.  Centralbl.,  14,  228,  1876.  Hofmann,  Ger.  Med., 
p.  631.     Gazz.  Lomb.,  J.  S.,  2,  38,  1875. 

LoMBROSA  ET  Erba.     Pharm.  Ztg.,  1879,  346, 

LucHSiNGER,  vide  Glatjse. 

LussAXA.  Gazz.  Lomb.,  1875.  Med.  Amtsbl.,  1875,  176.  Fried- 
rich's  Bl.,  1876,  166.  Hofmann,  Lehrbuch  d.  Gerichtl.  Med., 
p.  630.     Vide  Albertoni. 

LuxARDO,  O.  Gazz.  Chim.,  13,  94.  Journ.  Chem.  Soc,  44,  1156, 
1883. 

:\IAAS,  H.  Verhandl.  d.  Deutsch.  Chir.  Gesellsch.,  2,  167,  1883, 
Berlin,  med.  Centralbl.,  21,  715.  Centralbl.  f.  klin.  Med., 
1884,  9.  Archiv.  f.  klin.  Chir.,  29,  531,  1883.  Chem.  Cen- 
tralbl., 30,  14,  712,  1883;  1884,  925.  Chem.  Jahrb.,  1883, 
1359.  Deutsch.  med.  Ztg.,  1,  130,  1884.  Archiv.  d.  Pharm., 
222,  291.  1884.     Fortschritte  d.  Med.,  1883,  473;  2,  729,  1884. 

Magexdie.     Magendie's  Journ.  de  Phys.,  3,  81,  1823. 

Mallet,  vide  Cadeac. 

Mariko-Zuco,  F.  Eelazione  della  Esperienze  fatte  sulle  cosi 
dette  Ptomaine,  Roma,  1885.  Gaz.  chim.  ital.,  13,  431,  441, 
1881.  Ber.  d.  Chem.  Gesellsch.,  17,  142,  1043.  Arch.  d. 
Pharm.,  222, 197, 1884.  Jahrb.  f.  Chem.,  1883, 1359.  Deutsch. 
med.  Ztg.,  2,  245,  1884.  Journ.  Chem.  Soc.  Abstr.,  342, 1884. 
Yearbook  of  Pharmacy,  1884,  p.  80. 

Marquardt,  vide  Hager. 

Martens,  E.  v.     Virchow's  Archiv,  104,  174. 

Macthner,  J.     Annal.  d.  Chem.  u.  Pharm.,  166,  202. 


PTOMAINES.  305 

M.VYEK,  II.     Archiv.  f.  Experim.   Pathol,   u.  Pharmacol.,  21,  2, 

no,  1886.     Schmidt's  Jahrb.,  200.  l:«,  188G. 
Metschxikoff.     Virchow's  Archiv,  96. 
Meyer,  Jos.    Virchow's  Archiv,  4,  2^,  1852. 
Mikulicz.     Archiv.  f.  klin.  Chirurg.,  22,  253,  1878. 
MoBius.     Kicler  Zeitung,  Dec.  17,  1885. 
MoHRixc.     Acta  Physieo-Medica,  1744. 
MoRiGGiA.     Experiences  de  physiotoxicologie  sur  le  chlorhydrate 

de  trimethyl-vinyl-ammoniuiu  et  dc  chlorhydrate  de  trinie- 

thylamine.     Kome,  1885. 
MoRiGGiA   ET   Battistini.      Gazz.  chim.   ital.,    1875.      Ber.  d. 

Chem.  Gesellsch.,  9,  197.  1438,  1876.     Med.  Centralbl.,  1875, 

176.     Friedrich's  Bl.,  1876,  166.     Hofraann,  Gerichtl.  Med., 

p.  630.     Arch.  d.  Pharm.,  221,  416,  1883.     Maly's  Jahresb., 

1875,  77.     Bull.  d.  Sci.  Med.,  Bologna,  1876. 
Morrow.     New  York  Med.  Record,  1886,  2. 
MiJLLER,  A.     Chem.  Jahresb.,  1857,  402. 
MtJLLER,  L.     Experimentelle  Studien  fiber  die  Krankheits-  und 

Todesursache  in  Fauleuden  Stoflfen,  das  sogeuannte  Putride 

Gift.     3Iunchen,  1867 

MtJXTZ,  vi'le  SCHLOESIXG. 

Neelsen.     Archiv  f.  klin.  Chir.,  1884. 

Nexcki.  Ueber  die  Zersetzuug  der  Gelatine  and  des  Eiweisses 
bei  der  Fiiulniss  mit  Pankreas,  Bern,  1876.  Journ.  f.  Prakt. 
Chem..  26.  47,  1882.  Agric.  Chem.  Jahrb.,  25,  428,  1882. 
Schmidt's  Jahrb.,  196,  1882.  Ber.  d.  Chem.  Gesellsch.,  17, 
2605,  1884. 

Netter.     Archiv.  geu.,  13,  720,  1884. 

Newtox  axd  Wallace.    Phila.  Med.  News.  Sept.  25,  1886. 

NiCATi  ET  RiETSCH.  Journ.  de  Pharm.  et  de  Chim.,  12,  385, 
1885.  Archiv.  de  Pharm.,  224,  41.  Deutsch.  med.  Ztg.,  2, 
992,  1885.     Compt.  Rendus,  99,  928. 

NicoLAiER.     Deutsch.  med.  Wochenschr.,  1884,  No.  52. 

NiEMiLOWicz,  L.     Wiener  Acad.  d.  Wissensch.,  Mai  20.  1886. 

NovY,  F.  G.  Pharm.  Rundschau  (N.  Y.),  5,  152,  1887.  Vide 
Vaughan. 

Odermatt.  Zur  Keuntniss  der  Phenulbildung.  Inaug.  Disser- 
tation, Bern,  1878. 

Oeffinger.  H.  Die  Ptomaine  oder  Kadaver  Alkaloide.  Wies- 
baden, 1885. 

26* 


306  BIBLIOGRAPHY. 

Oemler.     Berl.  Arohiv,  1876-80. 

Ogston.     Britisli  Med.  Journ.,  1881. 

Ollivier.     Arinales  d'Hygiene,  20,  413. 

Oliveri.     Ber.  d.  Chem.  Gesellscli.,  19,  Eef.  876,  1886. 

Orfila.     Traite  des  Poisons.     3  ierae  ed.,  2,  492. 

OSER,  J.    Bull.  Soc.  Chim.,  10,  295,  1868.    Journ.  f.  Prakt.  Chem., 

103,  192,  1868.     Pol.  Centralbl.,  1869,  701. 
OsOL.     Experimentelle  Untersuchungen   iiber   das   Antliraxgift. 

Inaug.  Dissertation,  Dorpat,  1855. 
Otto.     Anleitung  zur  Ermittlung  d.  Giften,  Braunschweig,  1884. 
Panum.     Annal.  de  Chem.  et  de  Phys.,   [5]  9,  350.     Archiv.  d. 

Pharm.,  212,  88,  1878.     Schmidt's  Jahrb.,  9,  213,  1859.     Vir- 

chow's  Archiv,  10,  301;   15,441;    16;   25,308,433;    27,240; 

28,  29,  40;  60,  301,  1874.     Bidrag  til  Laeren  cm  den  saalna- 

lette  eller  septisce  Infection.     Bibliothek  of  for  Laegar,  1856. 
Passet.     Fortschr.  d.  Med.,  3,  33,  68. 
Pasquier.     Journ.  de  Pharmacie,  25. 
Paterno,  E.  et  Spica,  P.     Eicerche  suUa  genesi  delle  ptomaine. 

Accad.  dei  Lincei,  1881-82,  Eoma,  1882.     Gazz.  chim.  ital., 

12,  63,  1882.     Monit.  Scientif.,  131,  12,  580.     Chem.  Jahrb., 

1882,  1115.     Schmidt's  Jahrb.,  195,  10,  1882. 
Peter.    Bull,  de  I'Acad.,  [2]  15,  175,  1886. 
Petersen.     Nouveaux  documents  sur  Taction  du  venin  putride 

du  sang  qui  pourrit.     These  inaugurale.     Dorpat. 
V.  Planta,  Kekule.     Ann.  d.  Chem.  Pharm.,  89,  124,  1854. 
POHL,  A.    Petersb.  med.  Wochenschr.,  8,  30,  1883.    Ber.  d.  Chem. 

Gesellschr,  16,  1975,  975,  1883;    19,  1159,  1886.     Archiv.  d. 

Pharm.,  221,  760,  1883.     Chem.  Jahrb.,  1883,  1359.     Journ. 

Chem.  Soc,  44,  1157,  1883. 
POLLENDER.     Caspex's  Vierteljahrsschr.,  8,  103. 
POLLITZER.     Journal  of  Physiology,  7,  283,  1886. 
Pontopiddon.    Hosp.  Tid.,  3  R.,  1,  45,  1883. 
PoucHET,  A.  Gabriel.    Compt.  Rendus,  97,  1560;   99,  20,  848; 

100,  220,  362.     Journ.  de  Pharm.  et  de  Chim.,   [5]  9,  251. 

Archiv.  d.  Pharm.,  222,  327,  1884;  224,  92.     Gazz.  Hebdom., 

[2]  23,  5,  1886.     Journ.  de  Chim.  et  de  Pharm.,  12,  375, 1885. 

Archiv.  d.  Pharm.,  224,  92,  1886.     Monit.  Scientif.  d.  Quesne- 

ville,  1884,  253.     Journ.  Chem.  Soc,  46,  615,  1884. 
Radziszewski.     Annal.  d.  Chem.  u.  Pharm.,  203,  p.  330,  1880. 


PTOMAINES.  807 

Raffaelle,  a.  La  I'utrofazione  solto  il  Rapporto  della  Mc'dc- 
cine  legale,  Napoli.  1879,  p.  148.  Arcliiv.  d.  Plianri.,  221, 
416,  1888.     Giorn.  interiiaz.  della  sc.  med.,  1,  10,  11  DO,  1879. 

Raimondi,  C.     La  Salute,  [2|  18,  4,  5,  1884. 

Reiset.     Compt.  Rendus,  96,  ()82,  745. 

RiETSCH,  vide  NiCATI. 

RiNNE.     I]er.  d.  Cliem.  Gesellsch.,  18,  2520. 

RiTTER,  vide  Felt;^. 

RlTTHAUSEN.     Jouin.  f.  Piukt.  Cheiii.,  30,  o2. 

Robin.     L'Union  phann.,  23,  458.     Archiv.  d.  Pliann.,  209,  385, 

1881.  Gaz.  Med.  de  Paris,  [4],  309,  465,  1878. 

Roger  et  Ciiaerin.    Compt.  Rendus  Soc   Biol.,  1886,  607;  1887. 

Ber.  d.  Chem.  Gesellsch.,  20,  Ref.  438,  1887.     Med.  Record, 

32,  455,  1887.     Pharm.  Journ.  Trans.,  Dec.  1887. 
ROLOFF.     Der  Milzbrand,  1882. 

RoRSCH  u.  Fassbender.     Bcr.  d.  Chem.  Gesellsch.,  7,  1064. 
Roser.     Medical  Gazette,  1842-43. 
Rosenbach.     Mikroorgauismen    bei    den    Wundinfectionskrank- 

heiten  des  Menschen.     Wiesbaden,  1884. 
RouQUETTE.     Gaz.  Hebdom.,  |2|  23,  145,  1886. 
Salkowski,  E.  u.  H.     Ber.  d.  Chem.  Gesellsch.,  16,  1191,  1798, 

1883.     Fortsch.  d.  Med.,  2,  129,  1884.     Chem.  Jahrb.,  1883, 

1360.     Virchow's  Archiv,  102,  578. 
SCHAR.     Chem.  Ztg.,  1886. 
Scheibler.     Ber.  d.  Chem.  Gesellsch.,  3,  155.    Zeitsch.  f.  Zucker 

Ind.,  19,  425;  24,309. 
ScHEARER.     Report  of  Iowa  State  Board  of  Health,  188(5. 
SCHEURLEX.     Arbeiten  a.   d.  Chirurg.   Klinik   d.   Univ.   Berlin. 

III.  Theil. 
ScHiFFER.     Deutsch.  med.  Wochensch.,  1883. 
SCHLAGDENHAUFFER.     Jouru.  de  Pharni.  et  de  Chim.,  |5]  6,  128. 

Journ.  de  Pharm.    d'Alsace-Lorraine.      Archiv.   d.    Pharm., 

221,  146,  1883. 
SCHLAGDENHAUFFER   ET   Garnier.      Gaz.    des   Hopitaux,    88, 

1882.  Rev.  Med.de  Test,  15,  1882.    Deutsch.  med.  Ztg.,  1883, 
316. 

SCHL0E8SING  u.  MuNTZ.     Compt.  Reudus,  1879. 
Scheossberger,  J.      Archiv  f.  Physiol.  Heilk.,  1852.      Archiv  f. 
Pathol.   Anat.,  11,  569,  1857.     Archiv.  d.  Pharm.,  220,  270. 


308  BIBLIOGRAPHY. 

Schmidt's  Jahrb.,  97,  157,  1868.     Virchow's  Archiv,  11,  669, 

1857. 
Schmidt,  A.     Untersuchuagen  iiber  das  Sepsin.     Inaug.  Disser- 
tation.    Dorpat,  1869. 
Schmidt,  C.     Charal$;teristik  der  Epidemisclien  Cholera.     Leipzig 

u.  Mitau,  1850. 
Schmidt,  E.     Tagesbl.  d.  60ten  Versaraml.  d.  Deutsch.  Naturf.  u. 

Aerzte,  1887.     Pharm.  Eundsch.,  (N.  Y.),  5,  266,  1887. 
Schmidt  u.  Weiss.     Chem.  Centralbl.,  87,  1345. 
Schmidtmann.     Wilhelmshavener  Tageblatt,  Oct.  20,  1886. 
SciiMiEDEBERG  u.  Harnack.     Archiv.  f.  Exp.  Pathol,  u.  Pharm., 

6,101.     Chem.  Centralbl.,  1875,  629;    1876,554,560. 
Schmiedeberg  u.  Koppe.     Das  Muscarine.     Leipzig,  1869. 
Schmitz,  a.     Sur  la  question  du  poison  putride.     These  inaugu- 

rale.     Dorpat. 
Schollee,  M.     Experimentelle  Beitrage  zum  Studium  der  Sep- 

tischen  Infection.     Greifsw.  Hallilito.  Schrift,  1876. 
ScHREiBER.     Berlin.  Idin.  Wochenschr.,  1884.    Fortschr.  d.  Med., 

2,  383,  1884. 
ScHREiNER.     Ann.  d.  Chem.,  194,  68,  1878.     Schmidt's  Jahrb., 

191,  4. 
SCHULZE  u.  BosSHARD.      Zeitschr.   f.   Physiol.  Chem.,  10,   134, 

1886.     Deutsch.  med.  Ztg.,  1886,  437. 
Schumann.     Archiv.  f.  Med.  Erfahrung,  1829. 
ScHULZE.     Journ.  d.  Prakt.  Chem.,  27,  337. 
ScHULZE,  E.     Zeitschr.  f.  Physiol.  Chem  ,  11,  365,  61. 
ScHULZE,  F.  E.     Virchow's  Archiv,  104,  171. 
ScHWALCE,  C.     Archiv.  f.  Experim.  Pathol.,  105,  486.     Ber.  d. 

Chem.  Gesellsch  ,  20,  Eef.  591. 
ScHWANERT.     Ber.  d.  Chem.  Gesellsch.,  7,  1322,  1874.     Archiv. 

d.  Pharm.,  206,  272,  1875. 
SCHWENNINGER.    Ueber  die  Wirkung  Faulender  Organischer  Sub- 

stanzen  auf  den  Lebenden  Thierischen  Organismus.  Miinchen, 

1866.     Bayr.  Aerztl.  Int.  BL,  1866,  42,  47.     Schmidt's  Jahrb., 

4,  171,  12. 
Selmi,  F.     Ptomaine  od  Alcaloidi  cadaverici.     Bologna,  1881. 

Monit.  Scientif.,  [3]  8,  499,  877,  1400.     Chem.  Jahrb.,  1878, 

889,917,  1084.     Ber.  d.  Chem.  Gesellsch.,  6,  141,  1873;    8, 

1198;  9,  195, 197;  11, 808,  1691, 1838;  12, 297;    13,  206,  1880. 


PTOMAINES.  309 

Atti  d.  R.  Accad.  d.  Lincei,  [3]  2,  4,  6,  8.     Journ.  d'Hygi^ne, 

6,  305,  1882.     Acad.  d.  Biol.,  Dec.  12,  1S78. 
Di  alcuni  Criterii  per  la  Riccrca  degli  Alcaloidi  vegetali  in 

differenza  dolle  ptomaine.     Bologna,  1880. 
Alcaloidi  vcnetici  e  Sostanza  aniiloide  dall  albuinina  in  Putrc- 

fazione.     Roma,  1879.     Arch.  d.  Pharm.,  219,  415;    220,275. 

Gaz.  chim.  ital.,  11,  546, 1881 ;  1875,  396.    ('hem.  Jahrb.,  1881, 

1059.     Rendic.  d.  Accad.  Sci.  di  Bologna,  1875,  1876. 
Senator.     Berlin,  klin.  Wochenschr.,  1873,  No.  11. 
SlEDAMGROTZKY.     Zeitschr.  f.  Thiermedecin. 
Shakesheare.     .Journal  of  American  Med.  Assoc,  1887. 
SlEDLER.     Hufeland's  Journal. 
SiROTiNiN.     Zeitschr.  f.  Hygiene,  1. 
SoLDAlNl.     Giorn.  internaz  d.  Sci.  Med.,  [3]  10,  11,  1206,  1881. 

Gazz.  chim.  ital.,  11,  548;  13,  325.    Chem.  Jahrb.,  1883, 1358, 

1884,  975. 
SOLDAINI  E  Corona.     Giorn.  internaz.  d.  Sci.  Med.,  1882,  28. 

SONNEXSCHEIN,  vide  Zi'LZER. 

Spica.     Gazz.  chem.  ital.,  11,  486,  1881.    Ber.  d.  Chem.  Gesellsch., 

14,  27.     Chem.  Jahrb.,  1886.  975. 
Spica,  vide  Patero. 
Stanton.     Lancet  Clinic,  1887. 
Stevenson,  Th.     Brit.  Med.  Journ.,  1884. 
Sternberg.    Med.  News,  1887. 
Stich.     Annal.  d.  Charit.  Krankenli.,  3,  1!I2,  185.S. 
Strecker.     Anual.  d.  Chem.  u.  Pharm.,  123,  353;  148,  77. 
Sullivan.    Chem.  Jahrb.,  1858,  231. 
SzpiLMANN.     Zeitschr.  f.  Physiolog.  Chemie,  4. 
Tamassio.     Riv.  esper.  d.  frencatria  e  d.  med.  leg.,  [3]  8, 153, 1882. 
Tamba,  K.     Studien  iiber  das  Verhalteu  der  Ptomaine  bei  Foren- 

sisch-chemischen  Arbeiten.     Inaug.  Dissertation.     Erlangen, 

1887.     Archiv.  d.  Pharm.,  [3]  25,  408,  1887. 
Tanret.     Compt.  Rend.,  92,  1163.    Journ.  de  Pharm.  et  dc  Chim., 

[5]  4,  153.     Archiv.  d.  Pharm.  219,  369,  1881. 
Taylor.     On  Poisons.     London,  1875,  p.  533. 
Thiersch.     Pathol.-  Anatom.-  Beobachtungen  iiber  Pyaemia  nebst 

kritischen    Bemerkungen    iiber    die    Theorie    der    Pysemic. 

Miinchen,  1849. 
ToEPPER.     Die   neueren   Erfahrungen   iiber  die  Aetiologie  des 

Milzbrandes,  1883. 


810  BIBLIOGRAPHY. 

TOLLENS.     Zeitschr.  f.  Chem.,  1866,  516. 

Teottarelli.     Annal.  Univ.,  247,  329,  1879. 

Van  den  Coeptjt.     Du  Poison  qui  se  developpe  dans  les  viandes 

et  les  boudins  fumees.     Bruxelles,  1855.     Presse  Med.,  38,  17, 

1886. 
Van  Dissel,  vide  Wefers. 

Van  Ermengen.     Bull,  de  I'Acad.  d.  Med.  de  Belgique,  No.  12. 
Van  Gelder.     JSTieuw.  Tijdsclir.  voor  d  Pharm.  in  Nederl.,  1878, 

275. 
Vaughan,  Victor  C.     Zeitschr.  f.  Physiol.  Chem.,  10, 146,  1886. 

Schmidt's  Jahrb.,  209,  249,  1886.     Archiv.  d.  Pharm.,  224, 

413.     Journ.   Amer.   Med.   Assoc,   Sept.   17,   1887.     Journ. 

Anal.  Chem.,  1,  24,  1887. 
Vaughan,  V.  C,  and  Novy,  F.  G.     First  Quarterly  Eeport  of 

Michigan  Laboratory  of  Hygiene,  1888.     Pharm.  Rundschau, 

(N.  Y.),  6,  27,  1888. 
Veltz,  V.     Compt.  Eendus,  102,  880.     Ber.  d.  Chem.  Gesellsch., 

20,  Eef.  437. 
Villiers,  a.    Journ.  de  Pharm.  et  de  Chim.,  [5]  10,  257.    Archiv. 

d.  Pharm.,  223,  512,  1884.     Compt.  Eendus,  100,  91.     Bull. 

Soc.  Chim.,  43,  466. 
ViREY.     Trans.  London  College  of  Physicians,  109. 
ViRCHOW.     Ges.  Abhandl.  z.  Wissens.  Med.,  1856,  636.     Med. 

Eeform,   1884.      Berlin,    klin.   Wocheuschr.,    1885,   No.   48. 

Virchow's  Archiv,  104,  161. 
Wallace.    Phila.  Med.  News,  1887. 
Walz.     Chem.  Jahresb.,  1852,  552. 
Wasmund.     Chem.  Centralbl.,  1884,  975. 
Weber,  C.  0.     Deutsche  Klinik,  1864,  1865. 
Wefers,  H.  B.,  u.  Van  Dissel,  W.  J.    Nieuw.  Tijdsch.  voor 

Pharm.  Nederl.,  Fevr.,  1884.     Ber.  d.  Chem.  Gesellsch.,  1884, 

379. 
Weidenbaum.     Etudes  experimentales  sur  I'isolement  du  poison 

putride.     These  inaugurale.     Dorpat. 
Weiss.     Die  Neuesten  Vergiftungen  durch  Verdorbene  Wiirste. 

Carlsruhe,  1824. 
Wertheim.     Chem.  Jahresb.,  1851,  480. 
Westrumb.     Horn's  Archiv,  1828. 
Wicke.     Annal.  d.  Chem.  u.  Pharm.,  91,  121. 


LEUCOMAINES.  311 

WlEBECKE,  B.     Geschichtliclie  Entwicklung  unserer  Kenntniss 

der  Ptomaine  und  Verwaiultcr  Korper.     Berlin,  1S8G. 
WiLLGERODT,  C.      Uebcr  Ptomaine,  etc.,  Freiburg  1.  Br.,  1883. 

Deutsch.  mod.  Ztg.,  1883,  245.     Chem.  Zeit.,  6.  825. 
WiNDE,  P.  S.     Korp.  Tidende,  [2]  9,  17.     Schmidt's  Jahrb.,  194, 

251,  1882. 
Winkles,  G.  IT.     Annul,  d.  Chem.  u.  Pharm.,  93,  321. 
WOLCKENHAHR.     Corrcspondenzbl.  d.  Ver.  Anal.  Chem.,  1,  1878. 

Archiv.  d.  Pharm.,  221,  40G,  1883. 
WoLFENDEN,  E.  N.     Lancet,  1883. 
Wolff,  M.     Virchow's  Archiv,  103,  187;  104,  180. 
Wolff,  L.     Therap.  Gaz.,  Jan.  IG,  1888. 

WoRMLEY,  T.  G.     Micro-chemistry  of  Poisons.     Phila.,  1885. 
WURTZ,  A.     Annal.  d.  Chem.  u.  Pharm.,  Suppl.  6,  116,  197,  18G8; 

7,  88,  1870.     Compt.  Rendus,  65,  1015. 
YosHii,  T.,  vide  Kellner. 

Zeni,  G.     Gazz.  Ferrar.,  1882.     Arcliiv.  d.  Pharm.,  221.  485. 
ZiERO,  G.     Giorn.  interna/.,  d.  Sci.  Med.,  [2]  3,  319,  1880. 
Zuber,  O.     Gaz.  Hebdom.,  [2]  18,  26,  1881. 
ZiJLZER.     Archiv.  f.  Expcrim.  Pathol,  u.  Pharmalc,  8,  133,  1878. 
Zulzer  u.   Sonnenschein.     Berlin,  klin.  Wochensch.,  6,   128, 

1869. 


Leucomaines. 


D'Arsonval,  viile  Brown-Sequard. 

Baginsky.     Zeitschr.  f.  Physiol.  Chem..,  8,  395,  1884.      Ber.  d. 

Chem.  Gesellsch.,  18,  Ref.  356. 
Bandrowski,  F.  X.     Monatsch.  f.  Chem.,   8,   224.     Archiv.  d. 

Pharm.,  [3]  25,  739. 
Barbieri,  J.,  vide  Schulze. 
Barreswill.     Compt.  Rendus,  53,  246. 
Bechamp.     Compt.  Rendus,  94,  973,  1533,  1882. 
Bogoslowsky.     Archiv.  f.  Anat.  u.  Physiol.,  1872,  347. 
Bouchard,  Ch.     Compt.  Rendus,  102,  669,  727,  1127.     Ber.  d. 

Chem.  Gesellsch.,  20,  Ref.  437. 
Brown  Sequard  et  d'Arsonval.    Compt.  Rendus,  105,  1056 ; 

106,  106,  165,  1888. 
Calmeil.    Monit.  Sclent,  de  Quesneville,  1884,  392. 


312  BIBLIOGRAPHY. 

Capeajs^ica.     Zeitsclir.  f.  Physiol.  Cliem.,  4,  233. 

CHAEBKiT  ET  EoGER.  Compt.  Eendus,  1886,  607.  Ber.  d.  Chem. 
Gesellsch.,  20,  Eef.  438. 

Chittexdex,  R.  H.     Journ.  of  Pliysiology,  2,  28,  1879. 

Ceoez  et  Gratiolet.     Compt.  Eendus,  34,  729,  1852. 

DEMA2fT.     Zeitschr.  f.  Physiol.  Chem.,  3,  381. 

Eelenmeyer,  0.  u.  LiPP.  Annal.  d.  Chem.  u.  Pharm.,  219,  202, 
1883.     Ber.  d.  Chem.  Gesellsch.,  15,  1006,  1882. 

FiLEHifE,  W.,  vide  Schultzen. 

Fischer,  E.     Ber.  d.  Chem.  Gesellsch.,  15,  453.  1882;  17. 

Frey,  ]Max  Von.     Ber.  d.  Chem.  Gesellsch,,  19,  Eef.  505,  1886. 

Gautier,  a.  Bull.  Acad,  de  Med.,  Juillet  26,  1881,  [2]  10,  599, 
776,  947 ;  Juin,  1884,  1886.  Journ.  d.  Anat.  et  de  Phys.  de 
Ch.  Eobin.,  1881,  358.     Ber.  d.  Chem.  Gesellsch.,  20,  Eef.  337. 

Goeup-Besa>'ez  u.  Will.     Annal.  d.  Chem.  u.  Pharm.,  69,  117. 

Geatiolet,  ride  Cloez. 

HoRBACZEWSKi.  Monatsh.  f.  Chem.,  8,  4.  Pharm.  Journ.  Trans., 
[3]  18,  70.     Ber.  d.  Chem.  Gesellsch.,  20,  Eef.  723,  1887. 

Jones,  Bexce.     Journ.  Chem.  Soc,  15,  78,  1862;  [2]  6,  211, 1868. 

Kayser.     Ber.  d.  Chem.  Gesellsch.,  1S81,  2308. 

KossEL,  A.  Zeitschr.  f.  Physiol.  Chem.,  3,  284;  4,  290;  5,  152, 
6, 422 ;  7,  57  ;  10,  205,  248 ;  12,  241, 1888.  Ber.  d.  Chem.  Ge- 
sellsch., 1880,  1879;  1882,1770;  18,  79,  1918;  19,  Eef.  316 ; 
20,  3356. 

Keamee,  G.,  u.  Piknee,  A.  Ber.  d.  Chem.  Gesellsch.,  2,  401, 
1869 ;  3,  75,  1870. 

Ladenbijeg,  a.  and  Abel,  J.  Ber.  d.  Chem.  Gesellsch.,  21, 
758,  1888. 

Liebermaxn,  L.     Ber.  d.  Chem.  Gesellsch.,  21,  598,  1888. 

]\Iaecet.  Essay  on  the  Chemical  History  and  Chemical  Treat- 
ment of  Calculous  Disorders.     London,  1819. 

Mitchell,  S.  Weie,  and  Eeicheet,  E.  T.  Eesearches  upon  the 
Venoms  of  Poisonous  Serpents.  Smithsonian  Contributions 
to  Elnowledge,  1886. 

MoNAEi.  Gazz.  Chim.  Ital.,  17,  367,  1887.  Journ.  Chem.  Soc. 
Abstr.,  1887,  615;  1888,  174.  Ber.  d.  Chem.  Gesellsch.,  21, 
Eef.  143,  225,  1888.  Atti  d.  E.  Ace.  d.  Lincei  Endt.,  2,  202, 
1886. 

MoEiN,  E.  Ch.  Compt.  Eendus,  105,  Nov.  21,  1887 ;  106,  360, 
1888. 


l.EUCOM  AIXES.  313 

Nageli,  E.,  eide  Schulze. 

Nkubauer.     Zeitschr.  f.  Anal.  Chem.,  6,  33;  7.  398. 
Ordoxxeau.     Bull.  Soc.  Chim.,  45,  333,  188G. 
Oser.     Wiener  Akad.  Ber.,  2,  48;),  1867. 
PiCARD.     Ber.  d.  Chem.  Gesellsch.,  7,  1714,  1874. 
PiN'XER,  A.,  vide  Kramer. 
Vox  Planta,  a.,  vide  Schulze. 
Pollitzer.     Journ.  of  Pbyj>iology,  7,  284. 

PouCHET,  Gab.     Ber.  d.  Chem.  Geaellsch.,  17,  Ref.  49.     Contri- 
bution a  I'etude  des  matieres  extractives  de   I'urine,  Paris, 

1880. 
Reichekt,  E.  T.,  vide  Mitchell. 
Reixke,  J.,  u.  RoDEWALD,  H.     Untersuchungen  aus  d.   Botan. 

Laborat.  in  Gottingen,  2,  47. 
RoDEWALD,  H.,  vide  Reinke. 
Salkowski,  E.     Virchow's  Archiv,  50,  195. 
Salomox,  G.     Ber.  d.  Chem.  Gesellsch.,  1878,  -574;  16,  195,  1883 ; 

18,  3406.     Archiv.  f.  Physiol.,  1882,  1884.     Zeitschr.  f.  klin. 

med.,  7  Suppl.  Heft.,  p.  68, 1884.     Zeitschr.  f.  Physiol.  Chem., 

2,90;  11,  410,  1887.     Archiv  f.  Anat.  u.  Physiol.,  Physiol. 

Abtheil.,  1878,  320.     Yerhandlung.  d.  Physiol.  Gesellsch.  zu 

Berlin,  1880-81.     Ber.  d.  chem.  Gesellsch.,  21,  Ref.  24,  1888. 
Salomox  u.  Krause.     Ber.  d.  Chem.  Gesellsch.,  1879,  95. 
ScHAR,  E.     Chemiker  Zeitung,  1886,  Xo.  32. 
Scherer.     Annal.  d.  Chem.  u.  Pharm.,  73,  328;  107,  314;  112. 

257,  276. 
Schmidt,  E.     Annal.  d.  Chem.  u.  Pharm.,  217,  270,  308.     Bull. 

Soc.  Chim.,  40,  379. 
Schreixer,  Ph.     Annal.  d.  Chem.  u.  Pharm.,  194,  68,  1878. 
Schultzex,  0.,  u.  Filehxe,  W.    Ber.  d.  Chem.  Gesellsch.,  1, 150, 

1868. 
Schulze,  E.     Zeitschr.  f.  Physiol.  Chem.,  U,  61,  365. 
Schulze,  E.,  u.  Barbieri,  J.     Ber.  d.  Chem.  Gesellsch.,  16, 1711, 

1883.     Journ.  f.  Prakt.  Chem.,  [2]  25,  145 ;  27,  337.    Zeitschr. 

f.  Physiol.  Chem. 
Schulze,  E.  u.  Bosshard,  E.     Zeitschr.  f.  Physiol.  Chem.,  10, 

80,  86, 1886.     Ber.  d.  Chem.  Gesellsch.,  19,  261,  498.  1886. 
Schulze,  E.  u.  Nageli,  E.     Zeitschr.  f.  Physiol.  Chem.,  U,  201, 

1887. 

27 


314  BIBLIOGRAPHY. 

ScHULZE,  E.  u.-VoN  Planta,  a.     Zeitschr.  f.  Physiol.  Chem.,  10, 

326.     Ber.  d.  Chem.  Gesellsch.,  19,  Ref.  772,  1886. 
SCHIJTZENBERGEE.     Bull.  Soc.  Chim.,  7,  192 ;  21,  204. 
Steeckee.     Anual.  d.  Chem.  u.  Pharm.,  118,  152. 
Takeet.     Compt.  Eendus,  100, 1540  ;  106,  418,  1888. 
Thudichum,  L.  J.  W.     Grundziige  d.  Anatom.  u.  klin.  Chemie. 

Berlin,  1886.     Annals  of  Chemical  Medicine,  1,  160-174, 1879. 
TiCHOMiEOFF.     Zeitschr.  f.  Physiol.  Chem.,  9,  518,  566.     Ber.  d. 

Chem.  Gesellsch.,  19,  Ref.  315,  1886. 
Ungee.     Anual.  d.  Chem.  u.  Pharm.,  59,  58. 
Veltz,  V.     Compt.  Eendus,  102,  880.     Ber.  d.  Chem.  Gesellsch., 

20,  Ref.  437. 
Weidel,  H.     Annal.  d.  Chem.  u.  Pharm.  158,  353,  1871. 
Wellee,   a.     Ber.  d.   Chem.    Gesellsch.,  20,  2097.      Archiv  d. 

Pharm.,  [3]  25,  824. 
Will,  vide  Goeup-Besanez. 

Wolfenden,  R.  N.     Journ.  of  Physiology,  7,  327. 
WuETZ,  R.     Compt.  Rendus,  106,  213,  363,  1888. 
Zalesky.     1866. 


INDEX. 


AEROBIC  bacteria,  16 
Alcoholic    fermentation,    bases 
in,  170 
Alkaloids,    interference   in  reactions 

of,  by  ptomaines,  121 
Aniphi-creatine.  274 
Ana(irol)ic  bacteria,  IG 
Animal  chinoidine,  23,  28:> 
Anthrax,  95;  theory  of,  87 
Apricots,  poisonous,  52 
Atropine-like  ptomaines,  24,  110 
Autogenous  diseases,  13 
Azulniic  acid,  273 

BACILLUS  butyricus,  16 
Bacon,  poisonous,  51 
Betaine,  195 
Bibliography  of  leiicomaines,  311 

of  ptomaines,  296 
Biliousness,  292 
Blood,  leucomaines  in,  284 
Bread,  poisonous,  84 
Brieger's  method,  130 

CADAVERINE,  160 
Caffeine,  251 
Canned  meats,  poisonous,  51 
Caproylamine,  148 
Carbon  monoxide  in  expired  air,  277 
Carbonic  acid,  277 
Carnine,  262 
Caseic  acid,  17 

Charcot-Neumann,  crystals  of,  265 
Cheese,  poisonous,  52 
Cholera,  96 

blue,  101 

infantum,  107 

red,  99 
Choline,  184 

decompositions  of,  189 

group,  179 

constitution  of,  199 
("olchicine-like  ptomaines,  118 
Colds,  292 
Collidine,  148 

Coniine-like  ptomaines,  26,  110 
Corn-meal,  ptomaines  in,  31 
Creatine,  174,  245 


Creatinine,  174,  group,  268 
Cruso-creatinine,  271 
Cyanogen,  role  of,  271 

DELPHININE-LIKE    ptomaines, 
117 
Diamines,  154 
Diethylaraine,  146 
Dimethylamine,  142 
Dimethyl-xanthine,  258 
Disease,  relation  of  ptomaines  to,  K6 
Dragendorff's  method,  129 

I? EL,  poisonous,  40 
!i     Ethylamine,  145 
Ethyleneimine,  267 
Ethylidenediamine,  154 
Expii'ed  air,  leucomaines  in,  277 

FEVER  of  exhaustion,  274 
of  fatigue.  293 
of  non-elimination,  294 

GADININE,  204 
Galactine,  284 
Gautier  and  Etard,  methods  of,  133 
Gautier,  extraction,  of  leucomaines, 

269 
Germ-diseases,  classification  of,  93 
Germs,  relation  of,  to  disease,  87 
Goose-grease,  poisonous,  50 
Guanine,  243 

HAM,  poisonous,  46 
Heteroxanthine,  255 
Hexylamine,  148 
Historical  sketch  of  ptomaines,  18 
Hydrocollidine,  151 
Hydrocyanic  acid,  271 
Hypoxanthine,  236 

ICE-CREAM,  poisonous,  80 
Immunity  by  intoxication  with 
ptomaines,  108 
Infectious  diseases,  1 3 

definition  and  classification,  93 
Iso-amylamine,  147 
Iso-cyanacetic  acid,  2SS 


316 


INDEX. 


1( 


OCH'S  rules,  86 


LACTOOHROME.  284 
Leucocytheemia,   urine  in,  228, 
248 
Leucomaines,  chemistry  of,  224 
extraction  of,  269 
of  uric  acid  group,  227 
pathological  importance  of,  289 
tables  of,  288 

MEAL  and  bread,  poisonous,  84 
Meat,  poisonous,  50 
Methylamine,  141 

carbylamine,  288 

guanidine,  172 

hydantoin,  276 

uramine,  173 

xanthine,  249,  255 
Milk,  poisonous,  60 

leucomaines  in,  284 
Monamines,  141 
Morphine-like  ptomaines,  115 
Muscarine,  198 
Mussel,  poisonous,  34 
Mutton,  poisonous,  51 
Mycoderma  aceti,  16 
Mydatoxine,  199 
Mydaleine,  216 
Mydine,  177 
Mytilotoxine,  39,  202 

"VTARCOTIC  base  of  Panum,  22 
IM     Neelsen's  classification,  93 
Neuridine,  166 
Neurine  179 

OSER'S  base,  176 
Oxygenated  bases,  177 
Oysters,  poisonous,  40 

PARAXANTHINE,  258 
Parvoline,  152 
Pentamethylenediamine,  161 
Peptones,  poisonous  nature  of,  286, 

291 
Peptotoxine,  222,  291 
Piperidine,  synthesis  of,  164 
Poisonous  foods,  34 
Propylamine,  147 
Protamine,  267 
Pseudoxanthine,  265 
Ptomaine,  definition  of,  15 
table  of,  224 


Ptomaines,  extraction  of,  125 

remarks  upon,  134 
Puerperal  fever,  108 
Putrescine,  156 
Putrid  poison  of  Panum,  20 

SALIVA,  leucomaines  in,  282 
Samandarine,  287 
Saprine,  169 
Sausage,  poisonous,  40 
Sebacic  acid,  18 
Sepsine,  23 
Septicine,  148 
Septicsemia,  109 
Spasmotoxine,  148 
Spermine,  265 
Spleen,  leueomaine  in,  284 
Stas-Otto  method,  127 
Strychnine-like  ptomaines,  30,  114 

TETANINE,  211 

±     Tetanizing  ptomaine,  31 

Tetanotoxine,  148 

Tetanus,  102 

Tetramines,  176 

Tetra-methyl-putrescine,  138 

Theine,  251 

Theobromine,  synthesis  of,  251 

Toxicology  of  ptomaines,  110 

Trimethylamine,  143 

Triethylamine,  146 

Trimethylenediamine,  158 

Typhoid  bacillus,  16 

Typhotoxine,  206 

fever,  105 
Ty  rosin,  178 
Tyrotoxicon,  57,  214 

UNDETERMINED      leucomaines, 
277 
ptomaines,  219 
Uremic  jaoisoning,  295 
Uric  acid,  254 

group  of  leucomaines,  227 
Urine,  leucomaines  in,  280 
Urotheobromine,  258 

VANILLA,  84 
Veal,  jDoisonous,  50 
Venoms  of  serjDents,  285 
Veratrine-like  ptomaines,  117 
Vernine,  245 

XANTHINE,  248 
Xantho-creatinine,  272 


CATALOGUE  OF  BOOKS 

PUBLISHED    BY 

LEA  BROTHERS   &  CO. 

(LATE    HENRY    C.    LEA's    SON    4    CO.) 


The  books  in  the  annexed  list  will  be  sent  by  mail,  post-paid,  to  nny 
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Jn  rfspo7ise  to  a  large  number  of  inquiries  for  a  finer  binding  than  is 
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reach  of  all  to  possess  a  library  attractiveto  the  eye  as  well  as  to  the  mind. 

Detailed  catalogues  furnished  or  sent  free  by  mail  on  application. 
LEA    BROTHERS    &    CO., 
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THE  MEDkTaL  news, 

A  WEEKLY  JOURNAL  OF  MEDICAL  SCIENCE, 

Published  every  Saturday,  co?itaining  2S-.32  large  double-columned 

quarto  piges  of  reading  matter  in  each  7iumber. 

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Edited  by  I.  MINIS  HAYS,  A.M.,  M.D. 
With  the  issue  of  January,  1888,  The   American   Jocrnal  of  the 
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•n       .  T  '>r  o  /«<x  /*      num.  m  ad- 

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vance. 


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2  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

ALLEN  (HAERISON).  A  SYSTEM  OF  HUMAN  ANATOMY. 
WITH  AN  INTRODUCTORY  SECTION  ON  HISTOLOGY,  by 
E.  O.Shakespeare,  M.D.  Comprising  813  double-columned  quarto 
pages,  with  380  engravings  on  stone  on  109  plates,  and  241 
•woodcuts  in  the  text.  In  six  sections,  each  in  a  portfolio.  Sec- 
tion I.  (Histology),  Section  II.  (  Bones  and  Joints),  Section  III. 
(Muscles  and  Fasciae),  Section  IV.  (Arteries,  Veins  and  Lymjha- 
tics).  Section  V.  (Nervous  System),  Section  VI.  (Organs  of  Sense, 
of  Digestion  and  Genito-Urinary  Organs,  Embryology,  Develop- 
ment, Teratology,  Post-Mortem  Examinations,  General  and  Clini- 
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AMERICAN  SYSTEM  OF  DENTISTRY.  In  treatises  by  varions 
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A  MERICAN  SYSTEMS  OF  GYNECOLOGY  AND  OBSTETRICS.  In 
treatises  by  the  most  eminent  American  specialists.  Gynecology 
edited  by  Matthew  D.  Mann,  A  M.,  M.D.,  and  Obstetrics  edited  by 
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taining 784  pages,  with  201  illustrations  and  3  colored  plates,  is  now 
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ings and  a  colored  plate  and  is  just  ready.  Vol.  II.  of  the  Gynb- 
COLOGT  contains  about  1175  pages  wi  h  350  engravings  and  4 
colored  plates  and  is  just  ready.  Vol.  II.  of  the  Obstetrics  ready 
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ASHHTJRST  (JOHN,  Jr.)  THE  PRINCIPLES  AND  PRACTICE  OF 
SURGERY.  FOR  THE  USE  OF  STUDENTS  AND  PRACTI- 
TIONERS. New  (fourth)  and  revised  edition.  In  one  large  and 
handsome  octavo  volume  of  1114  pages,  with  597  woodcuts. 
Cloth,  $6;  leather,  $7;  half  Russia,  $7  50. 

ASHWELL  (SAMUEL).  A  PRACTICAL  TREATISE  ON  THE  DIS- 
EASES OF  WOMEN.  Third  edition.  520  pages.  Cloth,  $3  50. 
A  SYSTEM  OF  PRACTICAL  MEDICINE  BY  AMERICAN  AUTHORS. 
Edited  by  William  Pepper,  M.D.,  LL.D.  In  five  large  octavo 
volumes,  containing  5573  pages  and  198  illustrations.  Price  per 
volume,  cloth,  $5  00;  leather,  $6  00;  half  Russia,  $7  00.  Sold  by 
subscription  only.     Address  the  publishers. 

ATTFIELD  (JOHN).  CHEMISTRY  ;  GENERAL,  MEDICAL  AND 
PHARMACEUTICAL.  Tenth  edition,  specially  revised  by  the 
Author  for  America  In  one  handsome  12mo.  volume  of  728 
pages,  with  87  illus.    Cloth,  $2  50  ;  leather,  $3  00. 

BALL  (CHARLES  B.)  DISEASES  OF  THE  RECTUM  AND  ANUS. 
In  one  12mo.  vol.  of  417  pages,  with  54  illus.  and  4  colored  plates. 
Just  ready.     Cloth,  $2  25.     See  Series  of  Clinical  Manuals,  p.  13. 

BAREIER  (FORDYCE).  OBSTETRICAL  AND  CLINICAL  ESSAYS. 
In  one  handsome  12mo.  volume  of  about  300  pages.  Preparing. 
BARLOW  (GEORGE  H.)  A  MANUAL  OF  THE  PRACTICE  OF 
MEDICINE.  In  one  8vo.  volume  of  603  pages.  Cloth,  $2  50. 
BARNES  (ROBERT).  A  PRACTICAL  TREATISE  ON  THE  DIS- 
EASES OF  WOMEN.  Third  American  from  3d  English  edition.  In 
one  8vo.  vol.  of  about  800  pages,  with  about  200  illus.    Preparing. 

BARNES  (ROBERT  and  FAN  COURT).  A  SYSTEM  OF  OBSTET- 
RIC MEDICINE  AND  SURGERY,  THEORETICAL  AND  CLIN 
ICAL.  The  Section  on  Embryology  by  Prof.  Milnes  Marshall. 
In  one  large  octavo  volume  of  872  pages,  with  231  illustrations. 
Cloth,  $5;  leather,  $6. 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS.  3 

•pARTHOLOW  (ROBERTS).     MEDICAL  ELECTRICITY.    A  PRAC- 
■^     TICAL  TREATISE  ON  THE  APPLICATIONS  OF  ELECTRICITy 

TO  MEDICINE  AND  SURGERY.     Third   edition.     In  one  8vo. 

vol.  of  .308  pages,  with  110  illustrations.    Cloth,  $2  50. 
NEW  REMEDIES  OF  INDIGENOUS  SOURCE,  THEIR  PHY- 


B 


SIOLOGICAL  ACTIONS    AND    THERAPEUTICAL   USES.      In 
one  octavo  volume  of  about  300  pages.      Preparitig. 
■pASHAM  (W.  R.)     RENAL  DISEASES  ;  A  CLINICAL  GUIDE  TO 
■^     THEIR  DIAGNOSIS  AND  TREATMENT.    In  one  12mo.  volume 
of  304  pages,  with  illustrations.     Cloth,  $2  00. 

"DELLAMY  (EDWARD).  A  MANUAL  OF  SURGICAL  ANATOMY. 
In  one  12mo.  vol.  of  300  pages,  with  50  illustrations.  Cloth,  $2  25. 

OPERATIVE  SURGERY.     Shortly.     See    Studeiits'  Series  of 

Manuals,  p.  14. 
ELL  (F.  JEFFREY).  COMPARATIVE  PHYSIOLOGY  AND  ANAT- 
OMY.     In   one  12mo.  volume  of  661  pages,  with    229  woodcuts. 
Cloth,  $2.     See  Stndetits'  Series  of  Manvah,  p.  14. 

■pLOXAM  (C.  L.)  CHEMISTRY,  INORGANIC  AND  ORGANIC. 
With  Experiments.  New  American  from  the  fifth  London  edition. 
In  one  handsome  octavo  volume  of  727  pages,  with  292  illustra- 
tions.    Cloth,  $2  ;  leather,  $3 

■pRISTOWE  (JOHN  SYER).  A  TREATISE  ON  THE  PRACTICE  OF 
MEDICINE.  Second  American  edition,  revised  by  the  Author. 
Edited  with  additions  by  James  H.  Hutchinson,  M.D.  In  one 
8vo.  vol.  of  1085  pp.     Cloth, $5;  leather,  $6;   half  Russia,  $6  50. 

"pROADBENT,  (W.  H.)  THE  PULSE.  Preparing.  See  Series  of 
Clinical  Manuals,  ^.  13. 

■pROWNE  (EDGAR  A.)  HOW  TO  USE  THE  OPHTHALMOSCOPE. 
Elementary  instruction  in  Ophthalmoscopy  for  the  Use  of  Students. 
In  one  small  12mo.  volume  of  116  pages,  with  35  illuat.    Cloth,  $1. 

•pRUCE  (J.  MITCHELL).  MATERIA  MEDICA  AND  THERA- 
PEUTICS.  Fourth  edition.  In  one  12mo.  volume  of  591  pages. 
Cloth,  $1  60.     See  Studetits'  Series  of  Manuals,  p.  14. 

•pRUNTON    (T.   LAUDER).      A  MANUAL    OF    PHARMACOLOGY, 

^  THERAPEUTICS  AND  MATERIA  MEDICA;  including  the 
Pharmacy,  the  Physiological  Action  and  the  Therapeutical  Uses  of 
Drugs.  New  (third  and  revised)  edition,  in  one  octavo  volume  of 
1305  pages,  with  2.30  illustrations.     Cloth,  $5  50;  leather,  $6  50, 

■pRYANT  (THOMAS).  THE  PRACTICE  OF  SURGERY.  Fourth 
American  from  the  fourth  English  edition.  In  one  imperial  octavo 
volume  of  1040  pages,  with  727  illustrations.  Cloth,  $6  50; 
leather,  $7  50;  half  Russia,  $8  00. 

■pUMSTEAD  (F.J.)  and  TAYLOR  (R  W.)  THE  PATHOLOGY  AND 

^     TREATMENT  OF  VENEREAL  DISEASES.     Fifth  edition,  re- 

•    vised  and  rewritten,  with  many  additions,  by  R.  W.  Taylor,  M.D. 

In  one  handsome  Svo.  vol.  of  898  pages,  with  139  illustrations,  and 

two  chromo-lithographic  plates  containing  13  figures.    Cloth,  $4  75  ; 

leather,  $5  75  ;  very  handsome  half  Russia,  $6  25. 


4  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

■DTJRNETT  (CHARLES  H.)  THE  EAR :  ITS  ANATOMY,  PHTSI- 
OLOGY  AND  DISEASES.  A  Practical  Treatise  for  the  Use  of 
Students  and  Practitioners.  Second  edition.  In  one  8vo.  vol.  of 
680  pp.,  with  lOTillus.    Cloth,  $4  ;  leather,  $5  ;  half  Russia,  $5  60. 

■pUTLTN,  (HENRY  T.)  DISEASES  OF  THE  TONGUE.  In  one 
pocket-size  12mo.  vol.  of  466  pp.,  with  8  col.  plates  and  3  woodcuts. 
Limp  cloth,  $.3  60.      See  Series  of  Clinical  Manuals,  p.  1.3. 

pARPENTER  WM.  B  )  PRIZE  ESSAY  ON  THE  USE  OF  ALCO- 

^  HOLIC  LIQUORS  IN  HEALTH  AND  DISEASE.  New  Edition, 
with  a  Preface  by  D.  F.  Condie,  M.D.  One  12mo.  volume  of  178 
jiages.    Cloth,  60  cents. 

PRINCIPLES  OF  HUMAN  PHYSIOLOGY.     A  new  American, 


from  the  eighth  English  edition.     In  one  large  8vo.  volume. 
pARTER  (R.  BRUDENELL)  AND  PROST  (W.ADAMS)     OPHTHAL 

MIC  SURGERY.     In  one  pocket-size  12mo.  volume  of  659  pages, 

with  91  engravings  and  one  plate.    Jrist  ready.     Cloth,  .$2  25.     See 

Series  of  Clinical  Manuals,  p.  1.3. 
pHAMBERS  (T.  K.)       A  MANUAL  OF  DIET  IN  HEALTH   AND 
^     DISEASE.    In  one  handsome  8vo.  vol.  of  302  pages     Cloth,  $2  75. 
pHAPMAN  (HENRY  C  )    A  TREATISE  ON  HUMAN  PHYSIOLOGY. 

In  one  octavo  volume  of  925  pages,   with  605  illustrations.     Cloth, 

$6  60  ;  leather,  $6  60. 

CHARLES    (T.    CRANSTOUN).      THE    ELEMENTS    OF    PHYSIO- 
LOGICAL  AND  PATHOLOGICAL  CHEMISTRY.     In  one  hand- 
some octavo  volume  of  461  pages,  with  38  woodcuts  and  one  colored 
plate.    Cloth,  3  60. 
pKURCHILL    (FLEETWOOD).     ESSAYS   ON    THE   PUERPERAL 
^     FEVER.    In  one  octavo  volume  of  464  pages.    Cloth,  $2  50. 
pLARKE  (W.  B.)   AND  LOCKWOOD   (C.  B.)      THE  DISSECTOR'S 
MANUAL.    In  one  12mo.  volume  of  396  pages,  with  49  illustrations. 
Cloth,  $1  50.     See  Students''  Series  of  Manuals,  p.  14. 

CLASSEN'S  QUANTITATIVE  ANALYSIS.    Translated  by  Edgar  F. 
Smith,  Ph.D.  Inone  12mo.  vol  of  324  pp.,  with  36  illu.=  .  Cloth.  $2  00. 
pLELAND   (JOHN).     A  DIRECTORY  FOR  THE  DISSECTION  OF 
^     THE  HUMAN  BODY.    In  one  12mo.  vol.  of  178  pp.    Cloth,  $125. 
pLOUSTON  (THOMAS  S.)      CLINICAL   LECTURES   ON    MENTAL 
'-'     DISEASES.    With  an  Abstract  of  Laws  of  U.  S.  on  Cu.=tody  of  the 
Insane,  by  C.  F.  Folsom,  M.D.    In  one  handsome  octavo  vol.  of  641 
pages,  illustrated  with  woodcuts  and  8  lithographic  plates.     Cloth, 
$4  00.     Dr.  Folsom's  Abstract  is  also  furnished  separately  in  one 
octavo  volume  of  108  pages.     Cloth,  $1  60. 

CLOWES  (FRA.NK).  AN  ELEMENTARY  TREATISE  ON  PRACTI- 
CAL  CHEMISTRY  AND  QUALITATIVE  INORGANIC  ANALY- 
SIS. New  American  from  the  fourth  English  edition.  In  one  hand- 
some 12mo,  volume  of  387  pages,  with  65  illustrations.  Cloth,  $2  50. 
COATS  (JOSEPH).  A  TREATISE  ON  PATHOLOGY.  In  one  vol.  of 
829  pp. ,  with  339  engravings.  Cloth,  $5  60  ;  leather,  $6  50 
COHEN  (J.  80LIS).  DISEASES  OF  THE  THROAT  AND  NASAL 
PASSAGES.  Third  edition,  thoroughly  revised.  In  one  handsome 
octavo  volume.     Preparing. 

COLEMAN  (ALFRED).  A  MANUAL  OF  DENTAL  SURGERY  AND 
PATHOLOGY.  With  Notes  and  Additions  to  adapt  it  to  American 
Pr:ictice  By  Thos  C.  Stellwagen,  M  A.,  M.  D.,  D.D.S  .  Inonehand- 
some  8vo.  vol.  of  412  pp  ,  with  331  illus.    Cloth,  $3  25. 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS.  5 

pONDIE  (D. FRANCIS).  A  PRACTICAL  TREATISE  ON  THE  DIS- 
EASES  OF  CHILDREN.  Sixth  edition,  revised  and  enlarged.  In 
one  large  8vo.  vol.  of  719  pages.     Cloth,  $5  25  ;  leather,  £6  25. 

pOOPEK(B.B.)  LECTURESONTHEPRINCIPLES  ANDPRACTICE 

^     OF  SURGERY.    In  one  large  8vo.  vol.  of  767  pages.    Cloth,  S2  00. 

pDENIL  (V)    SYPHILIS:  ITS    MORBID  ANATOMY,  DIAGNOSIS 

^  AND  TREAIMENT.  Translated,  with  notes  and  additions,  Vy  J. 
Henry  C.  Simes,  M.D  ,  and  J.  William  White,  M  D.  In  one  Svo. 
volume  of  461  pages,  with  84  illn.otrations.     Cloth,  $3  75. 

pULLERIER  (A.)  AN  ATLAS  OF  VENEREAL  DISEASES.  Trans- 
luted  and  edited  by  Freeman  J.  BuMSTEAD,  M.D,  LL.D.  A  large 
quarto  volume  of  328  pages,  with  26  plates  containing  about  150 
figures,  beautifully  colored,  many  of  them  life-size.     Cloth,  $17. 

piTRNOW  (JOHN).  MEDICAL  APPLIED  ANATOMY.  In  pnss. 
See  StH</e?it's  Series  of  Manuals,  p.  14. 

"HALTON  (JOHN  C.)  DOCTRINES  OF  THE  CIRCULATION  OF 
THE  BLOOD.     In  one  handsome  12mo.  vol.  of  293  pp.    Cloth,  $2. 

A  TREATISE  ON  HUMAN  PHYSIOLOGY.     Seventh  edition, 

thoroughly  revised,  and  greatly  improved.  In  one  very  handsome 
Svo.  vol.  of  722  pages,  with  252  illustrations.  Cloth,  $5;  lea- 
ther, $6;   very  handsome  half  Russia,  $6  50. 

TjiNA  (JAMES  D.)    THE  STRUCTURE  AND  CLASSIFICATION  OF 

■^    ZOOPHYTES.    Withillust.onwood.  Inoneimp.4to.  vol.    CI. ,$4. 

"nAVIS(F..H)  LECTURES  ON  CLINICAL  MEDICINE.  Second 
edition     In  one  12rao.  volume  of  287  pages.     Cloth,  $1  75. 

TkE  LA  BECHZ'S  GEOLOGICAL  OBSERVER.   In  one  large  Svo.  vol 

■^    of  700  pages,  with  300illustrations.    Cloth,  $4. 

■nKAPER  (JOHN  C.)  MEDICAL  PHYSICS.  A  Text  book  for  Stu- 
dents  and  Practitioners  of  Medicine.  In  one  hnndsome  octavo  vol- 
ume of  734  pages,  with  376  illustrations.     Cloth,  $4. 

"nRTIITT  (ROBERT).  THE  PRINCIPLES  AND  PRACTICE  OF 
MODERN  SURGERY.  A  new  American  from  the  12th  London 
edition,  edited  by  Stanley  Boyd,  F.R  C.S.  In  one  large  octavo 
volumeof  965  pages,  with  373  illustrations.    Cloth,  $4;  leather,  $5. 

•niTNCAN  (J.MATTHEWS)  CLINICAL  LECTURES  ON  THE  DIS- 
EASES  OF  WO.MEN.  Delivered  in  St.  Bartholomew's  Hospital. 
In  one  octavo  volume  of  175  pages.    Cloth,  %\  50. 

"nTJNGLISON  (ROBLEY)  MEDICAL  LEXICON;  A  Dictionary  of 
Medical  Science.  Containing  a  concise  explanation  of  the  variou.s 
subjects  and  terms  of  Anatomy,  Physiology,  Pathology,  Hygiene, 
Therapeutics,  Pharmacology,  Pharmacy,  Surgery,  Obstetrics,  .Medi- 
cal Jurisprudence  and  Dentistry  ;  noticesof  Climate  and  of  Mineral 
Waters  ;  Formulae  forOfi&cinal,  Empirical  and  Dietetic  Preparations; 
with  the  accentuation  and  Etymology  ofthe  Terms,  and  the  French 
and  other  Synonymes.  Edited  by  R.  J.  Dunglison,  M.D.  In  one 
very  large  roj-al  Svo.  vol.  of  1139  pages.  Cloth,  $6  50  ;  leather, 
$7  50;   hulf  Russia,  $8. 

EDES' TEXT-BOOK  OF  THERAPEUTICS  AND  MATERIA  MFIDICA, 
In  one  Svo.   volume  of   544  pages.     Cloth,   S3  50 ;    leather,   $4  50. 
EDIS  (\RTHUR  W.)      DISEASES  OF  WOMEM.     A  Manual  for  Stu- 
dents  and  Practitioners.      In  one  hanilsome  Svo.  vol.  of  576  pp  , 
with  148  illustrations.     Cloth,  $3;  leather,  $4. 


6  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

pLLIS  (GEORGE  VINEE).  DEMONSTRATIONS  IN  ANATOMY. 
Being  a  Guide  to  the  Knowledge  of  the  Human  Body  by  Dissection. 
From  theeighth  and  revised  English  edition.  In  one  octavo  vol.  of 
716  pages,  with  249  illustrations.     Cloth,  $4  25  ;  leather,  $5  25. 

pMMET  (THOMAS  ADDIS).     THE  PRINCIPLES  AND  PRACTICE 

■"  OF  GYNAECOLOGY,  for  the  use  of  Students  and  Practitioners. 
Third  edition,  enlarged  and  revised.  In  one  large  8vo.  volume  of 
880  pages,  with  150  original  illustrations.  Cloth,  $5;  leather,  $6  ; 
half  Russia,  $6  50. 

■paiCHSEN  (JOHN  E.)  THE  SCIENCE  AND  ART  OF  SURGERY. 
A  new  American,  from  the  eighth  enlarged  and  revised  London 
edition.  In  two  large  octavo  volumes  containing  2316  pages,  with 
984  illus.    Cloth,  $9;  leather,  $11;  half  Russia,  raised  bands,  $12. 

■pARQUHARSON  (ROBERT).  A  GUIDE  TO  THERAPEUTICS. 
Fourth  American  edition,  specially  revised  by  the  Author.  In  one 
12mo.  volume  of  560  pages.     Preparing. 

pENWICK  (SAMUEL).  THE  STUDENTS'  GUIDE  TO  MEDICAL 
DIAGNOSIS.  From  the  third  revised  and  enlarged  London  edi- 
tion.   In  one  royal  12mo.  volume  of  328  pages.    Cloth,  $2  25. 

piNLAYSON  (JAMES).  CLINICAL  DIAGNOSIS.  A  Handbook  for 
Students  and  Practitioners  of  Medicine.  Second  edition.  In  one 
12mo.  volume  of  682  pages,  with  168  illustrations.     Cloth,  $2  60. 

pLINT    (AUSTIN).    A    TREATISE  ON  THE  PRINCIPLES    AND 

■'■  PRACTICE  OF  MEDICINE.  Sixth  edition,  thoroughly  revised 
and  largely  rewritten  by  the  Author,  assisted  by  William  H.  Welch, 
M.D  ,  and  Austin  Flint,  Jr.,  .D.  In  one  large  8vo.  volume  of 
1160  pages,  with  illustrations.  Cloth,  $5  50  ;  leather,  $6  50  ;  very 
handsome  half  Russia,  $7. 

A  MANUAL  OF  AUSCULTATION  AND  PERCUSSION  ;  of  the 

Physical  Diagnosis  of  Diseases  of  the  Lungs  and  Heart,  and  of  Tho- 
racic Aneurism.  Fourth  edition,  revised  and  enlarged.  In  one 
handsome  12mo.  volume  of  240  pages.     Cloth,  $1   75. 

A  PRACTICALTREATISE  ON  THE  DIAGNOSIS  AND  TREAT- 
MENT OF  DISEASES  OF  THE  HEART.  Second  edition,  enlarged. 
In  one  octavo  volume  of  550  pages.     Cloth,  $4  00. 

A   PRACTICAL  TREATISE  ON  THE  PHYSICAL  EXPLORA- 

TION  OF  THE  CHEST,  AND  THE  DIAGNOSIS  OF  DISEASES 
AFFECTING  THE  RESPIRATORY  ORGANS.  Second  and  revised 
edition.     In  one  octavo  volume  of  591  pages.     Cloth,  $4  50. 

MEDICAL  ESSAYS     In  one  12mo.  vol.,  pp.  210.    Cloth,  $138. 

ON    PHTHISIS:    ITS    MORBID    ANATOMY,     ETIOLOGY, 


ETC.     A  series  of  Clinical  Lectures.     In  one  8vo.  volume  of  442 
pages.     Cloth,  $3  60. 
lOLSOM  (0.  F.)     An  Abstract  of  Statutes  of  U.  S.  on  Custody  of  the 
Insane.     In  one  8vo.  vol.  of  108  pp.     Cloth,   $1  60.      Also   bound 
with  Clouiton  on  Insanity. 

lOSTER  (MICHAEL).  A  TEXT-BOOK  OF  PHYSIOLOGY.  English 
Student's  edition.  In  one  12mo.  volume  of  804  pages,  with  72 
illustrations.     Cloth,  $3. 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS.  7 

pOSTER  (MICHAEL).  A  TEXT-BOOK' OF  PHYSIOLOGY.  Third 
Americanfrom  the  fourth  English  edition,  edited  by  E.T.  Reichert, 
M.D.  In  one  large  12mo.  vol.  of  908  pages,  with  271  illustrations. 
Cloth,  f.3  25;  leather,  $3  75. 

pOTHERGILL'S  PRACTITIONER'S  HANDBOOK  OF  TREATMENT. 
New  (third)  edition.  In  one  handsome  octavo  volume  of  664  pages. 
Cloth,  $3  75  ;  leather,  $4  75. 

pDWNES  (GEORGE).  A  MANUAL  OF  ELEMENTARY  CHEMISTRY 
(INORGANIC  AND  ORGANIC).  Neweditioa.  Embodying  Watts' 
Pky steal  and  Inorganic  Chemistry.  In  one  royal  12mo.  vol.  of 
1061  pages,  with  168  illus.,  and  one  colored  plate.  Cloth,  $2  75; 
leather,  $3  25. 

pox  (TILBURY)  and  T.  COLCOTT.  EPITO.ME  OF  SKIN  DIS- 
EASES,  with  Formulae.  For  Students  and  Practitioners.  Third 
Am.  edition,  revised  by  T.  C.  Fox.  In  one  small  12mo.  volume 
of  238  pages.     Cloth,  $1  25. 

pRANKLAND  (E  )  and  JAPP  (F.  R.)     INORGANIC  CHEMISTRY^ 
In  one  handsome  octavo  vol.  of  677  pages,  with  51  engravings  and 
2  plates.     Cloth,  $3  75  ;  leather,  $4  75. 

pULLER  (HENRY).  ON  DISEASES  OF  THE  LUNGS  AND  AIR 
PASSAGES.  Their  Pathology,  Physical  Diagnosis,  Symptoms  and 
Treatment.  From2dEng.ed     In  1  .«<vo.  vol.,  pp.  475.   Cloth,  S3  50. 

piENEY(V.  P.)  ORTHOP.^DIC  SURGERY.  For  the  use  of  Prac- 
titioners  and  Students.     In  one  8vo    vol.  profusely  illus.      Prepg. 

piBSON'S  INSTITUTES  AND  PRACTICE  OF  SURGERY.  In  two 
octavo  volumes  of  965  pages,  with  34  plates.     Leather,  $6  50. 

riLUGE  (GOTTLIEB).  ATLAS  OF  PATHOLOGICAL  HISTOLOGY. 
Translated  by  Joseph  Leidy,  M.D.,  Professor  of  Anatomy  in  the 
University  of  Pennsylvania,  <!bc.  In  one  imperial  quarto  volume, 
with  320  copperplate  figures,  plain  and  colored.    Cloth,  $4. 

pOULD  (A.  PEARCE).  SURGICAL  DIAGNOSIS.  In  one  12mo. 
vol.  of  589  pages.    Cloth,  $2.    See  Sticdauts'  Series  of  Manuals  p.  14. 

pRAY  (HENRY).  ANATOMY,  DESCRIPTIVE  AND  SURGICAL. 
Edited  by  T.  Pickering  Pick,  F.R  C.S.  A  new  American,  from  the 
eleventh  Engli.^h  edition,  thoroughly  revised,  with  additions,  by 
W.  W.  Keen,  M  D.  To  which  is  added  Holden's  "Landmarks, 
Medical  and  Surgical."  In  one  imperial  octavo  volume  of  1098 
pages,  with  6S5  large  .and  elaborate  engravings  on  wood.  Cloth,  $6  ; 
leather,  $7  ;  very  handsome  half  Russia,  rai,*ed  bands,  $7  50.  The 
same  edition  is  also  issued  with  veins,  arteries,  and  nerves  distin- 
guished in  colors.  Price,  cloth,  $7  25;  leather,  $8  25;  half  Rus- 
sia, SS  75. 

pRAY   (LANDON  CARTEE).     A  PRACTICAL  TREATISE  ON  THE 

^  DISEASES  OF  THE  NERVOUS  SYSTEM.  In  one  handsome 
octavo  volume  of  about  600  pages.     Preparing. 

aREEN  (T.  HENRY).  AN  INTRODUCTION  TO  PATHOLOGY  AND 
.MORBID  ANWTOMY.  New  (si.xth)  American,  from  the  seventh 
London  edition.  In  one  handsome  octivo  volume  of  about  600 
pages,  with  about  175  illustrations.     Preparing. 

GREENE  (WILLIAM  H.)  A  M  ANUALOF  MEDICALCHEMISTRY. 
For  the  Use  of  Students.  Based  upon  Bowman's  Medical  Chem- 
istry.  In  one  12mo.  vol.  of  310  pages,  with  74  illus.    Cloth,  $175. 


8  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

pRIFFITH  (ROBERT  E.)     A   UNIVERSAL  FORMULARY,  CON- 
^    TAINING  THE  METHODS  OFPREPARING  AND  ADMINISTER- 
ING OFFICINAL  ANDOTHER  MEDICINES.   Thirdand  enlarged 
edition.     Edited  by  John  M.  Maisch,  Phar.D.     In  one  large  8vo. 
vol.  of  775  pages,  double  columns.     Cloth,  $4  50  ;  leather,  $5  50. 

GROSS  (SAMUEL  D.)  A  SYSTEM  OF  SURGERY,  PATHOLOGICAL, 
DIAGNOSTIC,  THERAPEUTIC  AND  OPERATIVE.  Sixth  edi- 
tion,  thoroughly  revised.  In  two  imperial  octavo  volumes  contain- 
ing 2382  pages,  with  1623  illustrations.  Strongly  bound  in  leather, 
raised  bands,  $15;  very  handsome  half  Russia,  raised  bands,  $lfi. 

A    PRACTICAL   TREATISE  ON   THE   DISEASES,    INJU- 

ries  and  Malformationsof  the  Urinary  Bladder, the  Prostate  Gland 
and  the  Urethra.  Third  edition,  thoroughly  revised  and  much 
condensed,  by  Samuel  W.  Gross,  M.D.  In  one  octavo  volume  of 
574  pages,  with  170  illus.     Cloth,  $4  50. 

A  PRACTICAL  TREATISE  ON  FOREIGN  BODIES  IN  THE 


AIR  PASSAGES.    Inone  8vo.  vol.  of  468  pages.    Cloth,  $2  75. 

GROSS    (SAMUEL   W.)      A   PRACTICAL   TREATISE   ON    IMPO- 
TENCE,   STERILITY,    AND    ALLIED    DISORDERS    OF    THE 
MALE  SEXUAL  ORGANS.     New  (third)  edition.     In  one  hand- 
some octavo  vol.  of  163  pages,  with  16  illustrations.     Cloth,  $1  50. 
TTABERSHON  (S.  0.)     ON  THE  DISEASES  OF  THE  ABDOMEN, 
■^    AND  OTHER  PARTS  OF  THE  ALIMENTARY  CANAL.    Second 
American,  from  the  third  English  edition.     In  one  handsome  8vo. 
volume  of  554  pages,  with  illus.     Cloth,  $3  50. 
TTAMILTON  (ALLAN  McLANE).     NERVOUS  DISEASES,   THEIR 
^   DESCRIPTION  AND  TREATMENT.    Second  and  revised  edition 
In  one  octavo  volume  of  598  pages,  with  72  illustrations.   Cloth ,  $4. 
TTAMILTON    (FRANK  H.)    A  PRACTICAL  TREATISE  ON  FRAC- 
•'-'•    TURES  AND  DISLOCATIONS.    Seventh  edition,  thoroughly  re- 
vised.    In  one  handsome  8vo.  vol.  of  998  pages,  with  352  illustra- 
tions.    Cloth,  $5  50;  leather,  $6  50;   very  handsome  half  Russia, 
$7  00. 
TTARTSHORNE  (HENRY).    A  HOUSEHOLD  MANUAL  OF  MEDI- 
^    CINE,  SURGERY,  NURSING,  AND  HYGIENE;    for  Daily  Use 
in  the  Preservation  of  Health,  and  Care  of  the  Sick  and  Injured. 
With  an  Introductory  Outline  of  Anatomy  and  Physiology.     In  one 
very  handsome  royal  octavo  volume  of  946  pages,  with  283  engrav- 
ings and  8  plates.     Cloth,  $4;  very  handsome  half  Morocco,  $5. 

ESSENTIALS  OF  THE  PRINCIPLES  AND  PRACTICE  OF 

MEDICINE.     Fifth  edition.     In  one  12mo.  volume,  669  pages, 
with  144  illustrations.     Cloth,  $2  75;  half  bound,   $3. 

A  HANDBOOK  OF  ANATOMY  AND  PHYSIOLOGY.     In  one 

]2mo.  volume  of  310  pages,  with  220  illustrations.     Cloth,  $1  76. 

A  CONSPECTUS  OF  THE  MEDICAL  SCIENCES.  Com- 
prising Manuals  of  Anatomy,  Physiology,  Chemistry,  Materia 
Medica,  Practice  of  Medicine,  Surgery  and  Obstetrics.  Second 
edition.  In  one  royal  12mo.  volume  of  1028  pages,  with  477  illus- 
trations.    Cloth,  $4  25  ;   leather,  $5  00. 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 


H 


H 


ERMANN  (L  )     EXPERIMENTAL  PHARMACOLOGY.     A  Hand- 
book of  the  Methods  for  Determining  the  Physiological   Actions  of 
I>nig'«.   Trnrslated  by  Rotert  Meade  Smith.  M.D.    In  one  12mo  vol. 
of  199  pages,  with  32  illustrations.     Cloth,  SI  50. 
ILL  (BEKKELEY).    SYPHILIS  AND  LOCAL  CONTAGIOUS  DIS- 
ORDERS      In  one  8vo.volumeof479  pages.     Cloth,  $3  25. 
TTlLLIEil  (IHOMAE;).  A  HANDBOOK  OF  SKIN  DISEASES.   2d  ed. 
In  one  royal  12mo.  vol.  of  353  pp.,  with  two  plntes.    Cloth,  $2  25. 
TTOBLYN  (RICHARD  D.)    A  DICTIONARY  OF  THE  TERMS  USED 
^   IN   MEDICINE  AND  THE  COLLATERAL  SCIENCES.     In  one 
12mo.  vol.  of  520  double-columned  pp.    Cloth,  $1  50  ;  leather,  $2 
TTODGE  (HUGH  L.)     ON  DISEASES  PECULIAR  TO  WOMEN,  IN- 
^    CLUDINfJ  DISPLACEMENTS  OF  THE  UTERUS.     Second  and 
revised  edition.     In  one  8vo.  volume  of  519  pages.     Cloth,  S4  50. 

THE  PRINCIPLES  AND  PR.4CTICE  OF  OBSTETRICS.   In  one 

large  4to.  vol.  of  542  double-columned  pages,  illustrated  with  large 
lithographic  plates  containing  159  figures  from  original  photographs, 
and  110  woodcuts.     Strongly  bound  in  cloth,  $14. 
TTOFFMANN    (FREDERICK)    AND   POWER   (FREDERICK  B  )     A 
^   MANUAL  OF  CHEMICAL  ANALYSIS,  as  Applied  to  the  Exaraina- 
tion  of  Medicinal  Chemicals  and  their  Preparations.    Third  edition, 
entirely  rewritten  and  much  enlarged.     In  one  handsome  octavo 
volume  of  621  pages,  with  179  illustrations.     Cloth,  $4  25. 
TJOLDEN(LUTHEE).   L.ANDMARKS,  MEDICAL  AND  SURGICAL. 
From  the  third  English  edition.     With  additions,  by  W.  W.  Keen, 
M.D.    In  one  royal  12mo.  vol.  of  148  pp.     Cloth,  $1. 
TTOLLAND  (SIR  HENRY).  MEDICAL  NOTES  AND  REFLECTIONS. 
•'-'•    From  3d  Englished.     In  one  8vo.  vol.  of  493  pp.     Cloth,  $3  50. 
TTOLMES  (TIMOTHY).    A  SYSTEM  OF  SURGERY.    With  notes  and 
additionsby  various  American  authors.  Edited  by  John  H.  Packard, 
M.D.     In  three  very  handsome  8vo.  vols,  containing  3137  double- 
columned  pages,   with  979  woodcuts   and  13   lithographic  plates. 
Cloth,  $18;  leather,  $21;  very  handsome  half  Russia,  raised  bands, 
$22  50.     For  sale  by  subscrtptioii  o>ily. 
TTORNER  (WILLIAM  E.)  SPECIAL  ANATOMY  AND  HISTOLOGY. 
Eighth  edition,  revised  and  modified.    In  twolarge8vo.  vols,  of  1007 
piiges,  containing  320  woodcuts.     Cloth,  $6. 
TTTJDSON  (A.)      LECTURES  ON    THE   STUDY    OF   FEVER.     In 
one  octavo  volume  of  308  pages.     Cloth,  $2  50. 

HUTCHINSON  (JONATHAN).  SYPHILIS.  In  one  pocket  size  12mo. 
volume  of  542  pagjs,  with  S  chromo-lithographic  plates.  Cloth, 
$2  25.  See  Series  of  Clinical  Manuals,  p.  13 
TTYDE  (JAMES  NEVINS).  A  PRACTICAL  TREATISEON  DISEASES 
•tl  OF  THE  SKIN.  New  (second)  edition  In  one  handsome  octavo 
volume  of  676  pages,  with  85  engravings  and  2  colored  plates. 
Cloth,  $4  50  ;   leather,  $5  50.     Just  ready. 

JONES  (0.  HANDFIELD).  CLINICAL  OBSERVATIONS  ON  FUNC 
TIONAL  NERVOUS  DISORDERS.  Second  American  edition.  In 
one  octavo  volume  of  340  pages.     Cloth,  $3  25. 

JULER  (HFNRY)  A  HANDBOOK  OF  OPHTHALMIC  SCIENCE 
AND  PRACTICE.  In  one8vo.  volume  of  460  pages,  with  125  wood- 
cuts, 27  chromo-lithographic  plates  test  types  of  Jaeger  and  Snellen 
and  Holmgren's  Color  blindness  test.    Cloth,  $4  50;  leather,  $5  50. 


10  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

TTING  (A.  F.  A)      A   MANUAL   OF   OBSTETRICS.     New   (third) 
edition.     In  one  12ino.  volume  of  373  pages,  with  102  illustrations. 

Cloth,  $2  25. 
TTLEIN  (E.)      ELEMENTS    OP    HISTOLOGY.     Third   edition.     In 

one  pocket-size  12mo.  volume  of  360  pages,  with  181  engravings. 

Cloth,  $1  50.     See  Students'  Series  of  Manuals,  page  14. 
T  ANDIS  (HENRY  G  )     THE  MANAGEMENT  OF  LABOR.     In  one 

handsome  12mo.  volume  of  329  pages,  with  28  illus.     Cloth,  $1  75. 
A  ROCHE  (R.)    YELLOW  FEVER.   In  two  8vo.  vols,  of  1468  pages. 

Cloth,  $7. 

-PNEUMONIA.    In  one  8vo.  vol.  of  490  pages-.     Cloth,  $3. 


L 


T  AURENCE  (J.  Z.)  AND  MOON  (ROBERT  C.)     A  HANDY-BOOK 

^  OF  OPHTHALMIC  SURGERY.  Second  edition,  revised  by  Mr. 
Laurence.     In  one  8vo.  vol.  pp.  227,  with  66  illus.     Cloth,  $2  75. 

T  AWSON  (GEORGE) .  INJURIES  OP  THE  EYE,  ORBIT  AND  EYE- 
LIDS.  Prom  the  last  English  edition.  In  one  handsome  octavo 
volume  of  404  pages,  with  92   illustrations.     Cloth,  $3  50. 

T  EA  (HENRY  0.)  SUPERSTITION  AND  FORCE  ;  ESSAYS  ON  THE 

^  WAGER  OF  LAW,  THE  WAGER  OF  BATTLE.  THE  ORDEAL 
AND  TORTURE.  Third  edition,  thoroughly  revised  and  greatly 
enlarged.    In  one  handsome  royal  12mo.  vol.  pp.  552.    Cloth,  $2  50. 

STUDIES  IN  CHURCH  HISTORY.    The  Riseof  the  Temporal 

Power — Benefit  of  Clergy — Excommunication.     New  edition.     In 
one  handsome  12mo.  vol.  of  605  pp.    Cloth,  $2  50. 

AN  HISTORICAL  SKETCH  OP  SACERDOTAL  CELIBACY 

IN  THE  CHRISTIAN  CHURCH.     Second  edition.     In  one  hand- 
some octavo  volume  of  684  pages.     Cloth,  $4  50. 

TEE  (HENRY)  ON  SYPHILIS.     In  one  8vo   volume  of  246  pages. 

^     Cloth,  $2  25. 

T  EHMANN  (C.  G.)     A  MANUAL  OF   CHEMICAL  PHYSIOLOGY. 

■'-'     In  one  8vo.  vol.  of  327  pages,  with  41  woodcuts.    Cloth,  $2  25. 

T  EISHMAN  (WILLIAM).  A  SYSTEM  OP  MIDWIFERY.  Includ- 
ing  the  Diseases  of  Pregnancy  and  the  Puerperal  State.  Third 
American,  from  the  third  English  edition.  With  additions,  by 
J.  S.  Parry,  M.D.  In  one  octavo  volume  of  740  pages,  with  205 
illustrations.     Cloth,  $4  50;  leather,  $5  50;    half  Russia,  $6. 

T  UCAS  (CLEMENT).  DISEASES  OF  THE  URETHRA.  Preparing. 
See  Series  of  Clinical  Maiiuals,  p.  13. 

T  UDLOW  (J.  L.)    A  MANUAL  OF  EXAMINATIONS  UPON  ANAT- 

■'-'  OMY,  PHYSIOLOGY,  SURGERY,  PRACTICE  OF  MEDICINE, 
OBSTETRICS,  MATERIA  MEDICA,  CHEMISTRY,  PHARMACY 
AND  THERAPEUTICS.  To  which  is  added  a  Medical  Formulary. 
Third  edition.  In  one  royal  12mo.  volume  of  816  pages,  with  370 
woodcuts.     Cloth,  $3  25  ;   leather,  $3  75. 

TYONS  (ROBERT  D.)     A  TREATISE  ON  FEVER.     In  one  octavo 

■'-'     volume  of  362  pages.     Cloth,  $2  25. 

■jWrAISCH  (JOHN  M.)  A  MANUAL  OP  ORGANIC  MATERIA  MED- 
ICA. New  (third)  edition.  In  one  handsome  12mo.  volume  of 
623  pages,  with  257beautiful  illustrations.    Cloth,  $3. 


LEA   BROTHERS  &  CO.'S  PUBLICATIONS.  11 

TUrARSH  (HOWARD).     DISEASES  OF  THE  JOINTS.     In  one  12mo. 

volume  of  468  pages,  with  64  illustrations  an  a  colored  plate. 
Cloth,  $2.     See  Series  of  Clinical  Manuals,  p.  13. 

TV/TAY  (C.  H.)    MANUAL  OF  THE  DISEASES  OF  WOMEN.    For  the 

•^  use  of  Students  and  Practitioners.  In  one  I2mo.  volume  of  342 
pages.     Cloth,  $1  75. 

•jVyTEIGS  (CHAS.D.)   ON  THE  NATURE,  SIGNS  AND  TREATMENT 

■'■OF  CHILDBED  FEVER.    In  oneSvo.  vol.  of  346  pages.    Cloth,  $2. 

■RyriLLZrv  (JAMES).  PRINCIPLES  OF  SURGERY.  Fourth  American, 
from  the  third  Edinburgh  edition.  In  one  large  octavo  volume  of 
688  page.s,  with  240  illustrations.     Cloth,  $3  7.5. 

IWriLLER  (JAMES).  THE  PRACTICE  OF  SURGERY.  Fourth 
American,  from  the  last  Edinburgh  edition.  In  one  large  octavo 
volume  of  682  pages,  with  364  illustrations.     Cloth,  S3  75. 

■R/riTCHELL  (S.  WEIR).     LECTURES   ON   NERVOUS   DISEASES, 

•'■'^  ESPECIALLY  IN  WOMEN.  Second  edition.  In  one  12mo.  vol- 
ume of  288  pages.     Cloth,  SI   75. 

"IVffGRRIS  (HENRY).     SURGICAL  DISEASES  OF  THE  KIDNEY. 

■*■*'■  12rao  ,  554  pages,  40  woodcuts,  and  6  colored  plates.  Cloth,  $2  25. 
See  Series  of  Clinical  Manuals,  p.  13. 

TWrULLER  (J.)  PRINCIPLES  OF  PHYSICS  AND  METEOROLOGY. 
In  one  large  8vo.  vol.  of  623  piiges,  with  538  cuts.     Cloth,  $4  50. 

■VTEILL  (JOHN)  AND  SMITH  (FRANCIS  G.)     A  COMPENDIUM  OF 

•"  THE  VARIOUS  BRANCHES  OF  MEDICAL  SCIENCE.  In  one 
handsome  12mo.  volume  of  974  pages,  with  374  woodcuts.  Cloth, 
$4  ;  leather,  raised  bands,  S4  75. 

"VTETTLESHIP'S  STUDENT'S  GUIDE  TO  DISEASES  OF  THE  EYE. 
New  (third;  edition.  In  one  royal  12rao.  volume  of  479  pages,  with 
164  illustrations,  test  types  and  formulae.     Cloth,  $2. 

■^rORRIS  AND  OLIVER  ON  THE  EYE.  In  one  8vo.  volume  of  about 
500  pages,  with  illustrations.     Prepiring. 

QWEN  (EDMUND).  SURGICAL  DISEASES  OF  CHILDREN.  12mo., 
525  pages,  85  woodcuts,  and  4  colored  plates.  Cloth,  $2.  See  Series 
of  Clinical  Ma7iuals,  p.  13. 

pARRISH  (EDWARD).  A  TREATISE  ON  PHARMACY.  With  many 
Formulae  and  Prescriptions.  Fifth  edition,  enlarged  and  thomughly 
revised  by  Thomas  S.  Wiegand,  Ph.G.  In  one  octavo  volume  of 
1093  pages,  with  257  illustrations.     Cloth;  $5  ;  leather,  $6. 

pARRY  (JOHN  S.)     EXTRA-UTERINE  PREGNANCY,  ITS  CLIN- 

^  ICAL  HISTORY,  DIAGNOSIS,  PROGNOSIS  AND  TREAT- 
MENT.     In  one  octavo  volume  of  272  p.iges.     Cloth,  $2  50. 

pARVlN  (THEOPHILUE).  THE  SCIENCE  AND  ART  OF  OBSTET- 
RICS.  In  one  handsome  8vo.  volume  of  697  pages,  with  214  en- 
gravings and  a  colored  plate.     Cloth,  $4  25  ;   leather,  $5  25. 

pAVY  (F.W.)    A  TREATISE  ON  THE  FUNCTION  OF  DIGESTION, 

■*•  ITS  DISORDERS  AND  THEIR  TREATMENT.  From  the  second 
London  edition.     In  one  octavo  volume  of  238  pages.    Cl(;th,  $2. 

PAYNE  (JOSEPH  FRANK).  A  MANUAL  OF  GENERAL  PATHOL- 
ogy.  Designed  as  an  Introduction  to  the  Piactice  of  Meilieine. 
Handsome  octavo  volume  of  about  550  pages  with  153  engravings. 
Fie})ariHg. 


12  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

pEPPER  (A.  J.)     FORENSIC  MEDICINE.     In  press.     See  Students' 
Series  of  Manuals,  p.  14. 

SUBGICAL  PATHOLOGT.    In  one  12mo.  volume  of  511  pages, 


with  81  illus.    Cloth,  $2.     See  Stirde?i.ts'  Series  of  Manuals,  p.  14. 
piCii    (T.    IICZEKING).      FRACTURES    AND     DISLOCATION^. 

In  one  12mo.  volume  of  530  pages,  with  93  illustrations,    Cloth,  $2. 

See  Series  of  Clinical  Manuals,  p.  13. 
piERIE  (WILLIAM).  THE  PRINCIPLES  AND  PRACTICE  OF  SDR 

GERY.    In  one  handsome  octavo  volume  of  780  pages,  with  316 

illustrations.     Cloth,  $3  75. 
pLAYFAIR  (W.  S  )     A  TREATISE  ON  THE  SCIENCE  AND  PRAC- 
■'■      TICE  OF  MIDWIFERY.     New  (fourth)  American  from  the  fifth 

English  edition.      Edited,  with  additions,  by  R.  P.  Harris,  M.D. 

In  one  octavo  volume  of  653  pages,  with  201  woodcuts  and  three 

plates.     Cloth,  $4;  leather,  $5;  half  Russia,  raised  bands,  $5  50. 

THE  SYSTEMATIC  TREATMENT  OF  NERVE  PROSTRA- 
TION AND  HYSTERIA.    In  one  12mo.  vol.  of  97  pages.    Cloth,  $1. 

pOLITZER  (ADAM).  A  TEXT-BOOK  OF  THE  EAR  AND  ITS  DIS- 
EASES. Translated  at  the  Author's  request  by  James  Patterson 
Cassells,  M.D.,  F.F.P.S.  In  one  handsome  octavo  volume  of  800 
pages,  with  257  original  illustrations.     Cloth,  $5  50. 

pOWER  (HENRY).  HUMAN  PHYSIOLOGY.  Second  edition.  In 
one  ]2mo.  volume  of  396  pages,  with  47  illustrations.  Cloth,  $1  50. 
See  Stui'Je7iis'  Series  of  Manuals,  page  14. 

pURDY  ON  BRIGUT'S  DISEASE  AND  ALLIED  AFFECTIONS  OF 

■'•      THE  KIDNEY.    Octavo,  288  pp.,  with  18  handsome  illus.    Cloth,  $2. 

"DALFE  (CHARLES  H.)  CLINICAL  CHEMISTRY.  In  one  12mo. 
volume  of  314  pages,  with  16  illustrations.  Cloth,  $1  60.  See 
Students'  Series  of  Manuals,  page  14. 

pAMSBOTHAM   (FRANCIS   H.)     THE  PRINCIPLES  AND  PRAC- 

■"  TICE  OF  OBSTETRIC  MEDICINE  AND  SURGERY.  Inoneim- 
perial  octavo  volume  of  640  pages,  with  64  plates,  besides  numerous 
woodcutsin  the  text.    Strongly  bound  in  leather,  $7. 

pEMSEN(IRA).  THE  PRINCIPLES  OF  CHEMISTRY.  New  (third) 
edition,  thoroughly  revised,  and  much  enlarged.  In  one  12mo. 
volume  of  318  pages.     Cloth,  $2. 

pEYNOLDS  (J.RUSSELL).  A  SYSTEM  OF  MEDICINE.  Edited, 
with  Notes  and  Additions,  by  Henry  Hartshorne,  M  D.  In  three 
larga  8vo.  vols.,  containing  3056  closely  printed  double-columned 
pages,  with  317  illustrations.  Per  volume,  cloth,  $5  ;  leather,  $6  ; 
very  handsome  half  Russia,  $6  50.      For  sale  by  subscription  only 

piCHARDSON  (BENJAMIN  W.)  PREVENTIVE  MEDICINE.  In 
one  octavo  vol.  of  729  pp.   Clo  ,  $4  ;  leather,  $5  ;  half  Russia,  $5  50. 

pOEERTS  (JOHN  B.)  THE  PRINCIPLES  AND  PRACTICE  OF 
SURGERY.  In  one  octavo  volume  of  about  500  pages,  fully  illus- 
trated.     Preparing. 

THE  COMPEND  OF  ANATOMY.     For  use   in   the   Diasecting 

Room  and  in  preparing  for  Examinations.     In  one  16mo.  volume  of 
196  piiges.     Limp  cloth,  75  cents. 


LEA  BROTHERS  &  CO.'S  PUBLICATIONS.  13 

•pOBERTS  (WILLIAM).   A  PRACTICAL  TREATISE  ON  URINARY 
■"     AND  RENAL  DISEASES,  INCLUDING  URINARY  DEPOSITS. 

Fourth   American,  from  the  fourth  London  edition.     In  one  very 

handsome  8vo.  vol.  of  609  pflges,  with  81  illuj-trationa.    Cloth,  $3  50. 
•pOBERTSON  (J.  McGREGOR).     PHYSIOLOGICAL   PHYSICS.     In 

one  12uio.  volume  of  637  pages,  with  219  illustrations.    Cloth,  $2  00. 

See  Students'  Series  of  Ma7iu(tls,  p.  14. 
•pOSS    (JAMES).      A    HANDBOOK   OF   THE    DISEASES   OF    THE 
•"    NERVOUS  SYSTEM.   In  one  handsome  octavo  volume  of  726  pages, 

with  1S4  illustrations.     Cloth,  $4  50;  leather,  $5  50. 
OAVAGE    (GEORGE  H.)      INSANITY  AND    ALLIED  NEUROSES, 
•^     PRACTICAL  AND  CLINICAL.    In  one  12mo.  volume  of  651  pag»8, 

wilh  18  typical  illustrations.     Cloth,  $2  00.     8ee  Series  of  Ch7iical 

Ma?i.nals,  p    13. 
OCHAFER    (EDWARD    A.)      THE   ESSENTIALS  OF  HISTOLOGY. 
•^     DESCRIPTIVE  AND  PRACTICAL.     For  the  use  of  Students.     In 

one  handsome  octavo  volume  of  246  pages,  with  281  illustrations. 

Cloth,  $2  25. 

qCHMITZ  AND  ZUMPT'S  CLASSICAL  SERIES.  In  royal  ISmo. 
*^  ADVANCED  LATIN  EXERCISES.  Cloth,  60  cents  ;  half  bound, 
70  cents. 

SALLUST.     Cloth,  eOcents;  half  bound,  70  cents. 

NEPO.S.     Cloth,  60  cents;  hal  f  bound,  70  cts. 

VIRGIL.     Cloth,  85  cents;   half  bound,  $1. 

CURTiUS.     Cloth,  80cents;  half  bound,  90  cents. 

a CJHOEDLER  (FREDERICK)  AND  MEDLOCK( HENRY) .  WONDERS 
OF    NATURE.     An    elementary   introduction  to    the  Sciences   of 
Physics,  Astronomy,  Chemistry,  Mineralogy,  Geology  ,  Botany,  Zool- 
ogy and  Physiology.    In  one  Svo.  vol.,  with  679  illus.    Cloth,  $3. 
OCHREIBER  (JOSEPH).     A  MANUAL  OF  TREATMENT  BY  MAS- 
^     SAGE  AND  METHODICAL   MUSCLE    EXERCISE.      Translated 
by  Walter  Mendelson,  M.D.,  of  New  York.     In  one  handsome  octavo 
volume  of  274    pages,  with    117   fine   engravings.       Cloth,    $2  75. 
OEILER  (CARL).     A  HANDBOOK  OF  DIAGNOSIS  AND  TREAT- 
^      MENT  OF  DISEASES  OF  THE  THROAT  AND  NASAL  CAV- 
ITIES.    New  (3d)  edition.     In  one  very  handsome  12mo.  volume 
of  about  300  pages,  with  about  100  illustrations.     In  Press. 
OERIES  OF  CLINICAL  MANUALS.     A  series  of  authoritative  mono- 
graphs  on  important  clinical  subjects,  in  12mo.  volumes  of  about  569 
j)ages,  well    illustrated.      The  following  volumes   are  now   ready  : 
Ball  on  the  Rectum  and  Anus,  $2  25  ;   Carter  and  Frost's  Ophthalmic 
Surgery,  $2  25  ;   Hutchinson  on  Syphilis  (S2  2.'))  ;  Marsh  on  Diseases 
of  the  Joints  (•*2);  Morris  on  Surgical  Diseases  of  the  Kidney  ($2  25); 
Owen  on  Surgical  Diseases  of  Children  ($2)  ;  Pick  on  Fractures  and 
Dislocations  ($2);   Butlin  on   the  T3ngue    ($.1  50) ;   Savage  on   In- 
sanity and  Allied  Neuroses   ($2),  and  Treves  on  Intestinal  Obstruc- 
tion ($2).     The  following  are  in  press:  Broadbenl  on  the  Pulse; 
Lucas  on  Diseases  of  the  Urethra. 
For  separate  notices,  see  under  various  authors'  names. 

SIMON  (W.)  MANUAL  OF  CHEMISTRY.  A  Guide  to  Lectures 
and  Laboratory  work  for  Beginners  in  Cheinistrj'.  A  Text-book 
specially  adapted  for  Students  of  Pharmacy  and  Medicine  New 
(2d)  edition.  In  one  8vo.  volume  of  480  pages,  with  44  wood- 
cuts and  7  colored  plates  of  deposits.    Cloth,  $3  25.  Just  ready. 


14  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

^KEY  (FREDERIC  C.)    OPERATIVE  SURGERY     In  one  8vo.  vol. 

•^     of  661  pages,  with  81  woodcuts.     Cloth,  $3  25. 

QJLADE  (CD.)  DIPHTHERIA;  ITS  NATURE  AND  TREATMENT. 
Second  edition.     In  one  royal  12mo.  vol.  pp.  158.     Cloth,  $1  25. 

OMITH   (EDWARD).    CONSUMPTION;   ITS  EARLY  AND  REME- 

^     DIABLE  STAGES.     In  one  8vo.  vol.  of  253  pp.     Cloth,  $2  25. 

OMITH  (J.LEWIS).    A  TREATISE  ON  THE  DISEASES  OF  IN- 

"^  FANCY  AND  CHILDHOOD.  New  (sixth)  edition,  revised  and 
enlarged.  In  one  large  8vo.  volume  of  867  pages,  with  40  illustra- 
tions.    Cloth,  $4  50  ;  leather,  ®5  50  ;  half  Russia,  $6. 

OMITH  (STEPHEN).  OPERATIVE  SURGERY.  New  (second)  and 
thoroughly  revised  edition.  In  one  very  handsome  8vo.  volume, 
of  892  pilges,  with  1005  illustrations.     Cloth,  $4;  leather,  $5. 

OTILIE  (ALFRED).     CHOLERA,  ITS  ORIGIN,  HISTORY,  CAUSA- 

•^  TION,  SYMPTOMS,  LESIONS,  PREVENTION  AND  TREAT- 
MENT.  In  one  handsome  12rao.  volume  of  163  pnges,  with  a  chart 
showing  routes  of  previous  epidemics.     Cloth,  $1  25. 

OTILLE  (ALFRED).  THERAPEUTICS  AND  MATERIA  MEDIC  A. 
Fourth  revised  edition.  In  two  handsome  octavo  volumes  of  1936 
pages.    Cloth, $10;  leather, $12;  very  handsome  half  Russia,  $13. 

OTILLE    (ALFRED)  AND  MAISCH  (JOHN  M.)     THE  NATIONAL 

•^  DISPENSATORY:  Containing  the  Natural  History,  Chemistry, 
Pharmacy,  Actions  and  Uses  of  Medicines.  Including  those  rec- 
ognized in  the  latest  Pharmacopoeias  of  the  United  States,  Great 
Britain  and  Germany,  with  numerous  references  to  the  French 
Codex.  New  (fourth)  edition,  revised  and  enlarged  with  an  Appen- 
dix. In  one  magnificent  imperial  octavo  volume  of  1794  pages, 
with  311  accurate  engravings  on  wood.  Cloth,  $7  25  ;  leather, 
raised  bands,  $8  ;  very  handsome  half  Russia,  raised  bands  and  open 
back,  $9.  Also,  furnished  with  Ready  Reference  Thumb-letter  Index 
for  $1  in  addition  to  price  in  any  of  the  above  styles  of  binding. 

OTIMSON    (LEWIS  A.)      A    TREATISE    ON    FRACTURES   AND 

"^  DISLOCATIONS.  In  two  handsome  octavo  volumes.  Vol.  I.,  Frac- 
tures, 582  pnges,  360  beautiful  illustrations.  Vol.  II.,  Dislocations, 
540  pp.,  163  illustrations.  Com-p\ete  •work,  just  ready ,  cloth,  $5  50; 
leather,  $7  50.     Either  volume  separately,  cloth,  $3  ;   leather,  $4. 

A  MANUAL  OF  OPERATIVE  SURGERY.    New  edition.    In 

one  royal  12mo.  volume  of  503  pages,  with  342  illustrations. 
Cloth,  $2  50. 

STUDENTS'  SERIES  OF  MANUALS.  A  series  of  fifteen  Manuals  by 
eminent  teachers  or  examiners.  The  volumes  are  pocket-size 
l2mos.  of  from  300-540  pages,  profusely  illustrated,  and  bound  in 
red  limp  cloth.  The  following  volumes  may  now  be  announced  : 
Bruce's  Materia  Medica  and  Therapeutics  (fourth  edition),  $1  50  ; 
Treves'  Manual  of  Surgery  (monographs  by  33  leading  surgeons), 
3  volumes,  each  $2  00  ;  Bell's  Comparative  Physiology  and  Anatomy, 
$2  00;  Robertson's  Physiological  Physics,  $2  00  ;  Gould's  Surgical 
Diagnosis,  $2  00;  Klein's  Elements  of  Histology  (3d  edition), 
$1  60;  Pepper's  Surgical  Pathology,  $2  00  ;  Treves'  Surgical  Ap- 
plied Anatomy,  $2  00  ;  Power's  Human  Physiology,  second  edition, 
$1  50;  Ralfe's  Clinical  Chemistry,  $1  50;  and  Clarke  and  Lock- 
wood's  Dissector's  Manual,  $1  60.  The  following  volumes  are  in 
press  :  Bellamy's  Operative  Surgery,  Pepper's  Forensic  Medicine, 
and  Curnow's  Medical  Applied  Anatomy. 
For  separate  notices,  see  under  various  authors'  names. 


LEA  BROTHERS  &  CO  'S  PUBLICATIONS.  15 

OTURGES  (OCTAVIUS).  AN  INTRODUCTION  TO  THE  STUDY 
■^  OF  CLINICAL  MEDICINE.  In  one  12ino.  vol.  Cloth,  $125- 
rjiAIT    (LAWSON).     DISEASES   OF    WOMEN    AND   ABDOMINAL 

SURGERY.    Handsome  octavo  vcluine,  GOO  pages,  fully  illustrated. 

Preparing. 

TANNER  (THOMAS  HAWKEP).  A  MANUAL  OF  CLINICAL  MEDl- 
CINE  AND  PHYSICAL  DIAGNOSIS.  Third  American  from  the 
second  revi.-;ed  Engli.'^h  edition.  Edited  by  Tilbury  Fox,  M.  D.  In 
one  handsome  12mo.  volume  of  362  pp.,  with  ill  us.     Cloth,  $1  50. 

ON  THE  SIGNS  AND  DISEASES  OF  PREGNANCY.    From 

the  second  English  edition.  In  one  8vo.  volume  of  490  pages,  with 
four  colored  plates  and  numerous  woodcuts.     Cloth,  $4  26. 

rPAYLOR  (ALFRED  S.)  MEDICAL  JURISPRUDENCE.  Eighth 
American  from  tenth  English  edition,  specially  revised  by  the 
Author.  Edited  by  John  J.  Reese,  M.D.  In  one  Large  octavo 
volume  of  937  pages,  with  70  illustrations.  Cloth,  $5;  leather, 
$6  ;   very  handsome  half  Russia,  raised  bands,  $6  50. 

ON  POISONS  IN  RELATION  TO  MEDICINE  AND  MEDICAL 

JURISPRUDENCE.  Third  American  from  the  third  London  edi- 
tion.  In  one  octavo  volume  of  788  pages,  with  104  illustrations. 
Cloth,  $6  50  ;  leather,  $6  50. 

THE  PRINCIPLES  AND  PRACTICE  OF  MEDICAL  JURIS- 

PRUDENCE.  Third  ed.  In  two  handsome  8vo.  vols,  of  1416  pp., 
with  188  illustrations.     Cloth,  $10;   leather,  $12. 

TAYLOR  (ROBiRT  W.).  A  CLINICAL  ATLAS  OF  VENEREAL 
AND  SKIN  DISEASES.  Including  Diagnosis,  Prognosis,  and 
Treatment  In  eight  large  folio  parts,  measuring  14  x  18  inches, 
and  comprising  192  beautiful  figures  on  58  full-pnge  chromo-litho- 
graphic  plates,  66  fine  engravings,  and  about  400  pages  of  text. 
Parts  I.  and  II.  are  just  ready  Price  per  part,  $2  50.  For  safe  by 
svbscriytion  only.  Address  the  Publishers.  Specimen  plates  by 
mail  on  receipt  often  cents. 

THOMAS  (T.  GAILLARD).  A  PRACTICAL  TREATISE  ON  THE 
DISEASES  OF  WOMEN.  Fifth  edition,  thoroughly  revised  and 
rewritten.  In  one  large  and  handsome  octavo  volume  of  810 
pages,  with  266  illustrations.  Cloth,  $6  ;  leather,  $6;  very  hand- 
some half  Russia,  $6  60. 

THOMPSON  (SIR  HENRY).  CLINICAL  LECTURES  ON  DISEASES 
OF  THE  URINARY  ORGANS.  Second  and  revised  edition.  In 
one  octavo  volume  of  203  pages,  with  illustrations.    Cloth,  $2  25. 

THOMPSON  (SIR  HENRY).  THE  PATHOLOGY  AND  TREAT- 
MENT  OF  STRICTURE  OF  THE  URETHRA  AND  URINARY 
FISTULjE.  From  the  third  English  edition.  In  one  octavo  vol- 
me  of  359    pages,  with  illustrations.     Cloth,  $3  60. 

TIDY  (CHARLES  MEYMOTT).  LEGAL  MEDICINE.  Volumes  I. 
and  II.  Two  imperial  octavo  volumes  containing  1193  pages,  with 
2  colored  plates.     Per  volume,  cloth,  $6;  leather,  $7. 

TODD  (ROBERT  BENTLEY) .  CLINICAL  LECTURES  ON  CERTAIN 
ACUTE  DISEASES.  In  oneSvo.  vol.  of  320  pp.,  cloth,  $2  50. 
TREVES  (FREDERICK).  A  MANUAL  OF  SURGERY.  In  Treatises 
by  33  leading  surgeons.  Three  12mo.  volumes,  containing  1866 
pages,  with  213  engravings.  Price  per  set,  $6.  See  Students' 
Series  of  Manuals,  p.  14. 

SURGICAL  APPLIED  ANATOMY.     In  one  12mo.  volume  of 

540  pages,  with  61  illustrations.  Cloth,  $2  00.  See  Students'  Series 
of  Manvals,  poge  14. 

INTESTINAL  OBSTRUCTION.     In  one  12mo.  volume  of  522 

pages,  with  60  illustrations.  Cloth,  $2  00.  See  Series  of  Clinical 
Manuals,  p.  13. 


16  LEA  BROTHERS  &  CO.'S  PUBLICATIONS. 

rjiUKE  (DANIEL  HACK) .  THE  IFLNUENCE  OF  THE  MIND  UPON 
THE  BODY.  Second  edition.  In  one  handsome  8vo.  vol.  of  467 
pnges,  with  2  colored  pla*es.     Cloth,  $3. 

TTAUGHAN  (VICTOR  C  ),  and   NOVY  (FEED'Z  G.)     PTOMAINES 
''      AND    LEUCOMAINES,    OR  PUTREFACTIVE    AND   PHYSIO- 
LOGICAL   ALKALOIDS.     In  one  handsome  12mo.  volume  of  311 
pages.     Cloth,  $1  75.     Juet  ready. 

T7ISITING  LIST.  THE  MEDICAL  NEWS  VISITING  LIST  for  1889. 
Thoroughly  revised.  48  pages  of  indispensable  data,  and  176  pages 
of  conveniently  ruled  and  classified  blanks  for  records.  Pocket,  pencil, 
catheter  scale,  and  erasable  tablet.  Three  styles  :  Weekly  (dated, 
for  30  patients)  ;  Monthly  (undated),  and  Perpetual  (undated). 
Each  in  one  vol.,  price,  $1  25.  With  thumb-letter  index  for  quick 
use,  25  cents  extra.  Special  rates  to  advance-paying  subscribers  to 
The  Medical  News  or  The  American  Journal,  or  both.     See  p.  1. 

WALSHE  (W.  H.)     PRACTICAL  TREATISE  ON  THE  DISEASES 

''''  OFTHEHEART  AND  GREAT  VESSELS.  3d  American  from  the 
3d  revised  London  edition.   In  one  8vo.  vol.  of420  pages.  Cloth,  $3. 

WATSON    (THOMAS).    LECTURES  ON  THE  PRINCIPLES  AND 

"'  PRACTICE  OF  PHYSIC.  A  new  American  from  the  fifth  and  en- 
larged English  edition,  with  additions  by  H.  Hartshorne,  M.D.  In 
two  large  8vo.  vols,  of  1840  pp.,  with  190  cuts.    Clo.,  $9  ;  lea.,  §11. 

TTTTELLS  (J.  SOELBERG).    A  TREATISE  ON  THE  DISEASES  OF 

"*    THE  EYE.    New  (fifth)  edition,  thoroughly  revised.    In  one  large 

and  handsome  octavo  vol.  of  about  800  pages,  with  colored  plates 

and  about  300  woodcuts,  as  well  as  selections  from  the  test-types 

of  Jaeger  and  Snellen. 

WEST  (CHARLES).     LECTURES  ON  THE  DISEASES  PECULIAR 

"'  TO  WOMEN.  Third  American  from  the  third  English  edition.  In 
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WINCKEL  ON  PATHOLOGY  AND  TREATMENT  OF  CHILDBED. 
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WOHLER'S  OUTLINES  OF  ORGANIC  CHEMISTRY.  Translated 
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W GODHEAD  (G.  SIMS).  PRACTICAL  PATHOLOGY.  A  Manual 
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YEAR-BOOK  OF  TREATMENT  FOR  1887.  A  Comprehensive  and 
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